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Sample records for system cns human

  1. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; Kokki, Hannu; Kokki, Merja; Danhof, Meindert; van Hasselt, Johan G. C.; de Lange, Elizabeth C. M.

    2018-01-01

    Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human,

  2. Central Nervous System (CNS Disease Triggering Takotsubo Syndrome

    Directory of Open Access Journals (Sweden)

    Josef Finsterer

    2016-01-01

    Full Text Available Takotsubo syndrome (TTS is usually triggered by psychological or physical stress. One of the many physical sources of stress are central nervous system (CNS disorders. CNS disorders most frequently triggering TTS include subarachnoid bleeding, epilepsy, ischemic stroke, migraine, and intracerebral bleeding. More rare CNS-triggers of TTS include posterior reversible encephalopathy syndrome (PRES, amyotrophic lateral sclerosis, encephalitis, or traumatic brain or spinal cord injury. TTS triggered by any of the CNS disorders needs to be recognized since adequate treatment of TTS may improve the general outcome from the CNS disorder as well. Neurologists need to be aware of TTS as a complication of specific CNS disorders but TTS may be triggered also by CNS disorders so far not recognised as causes of TTS.

  3. In vivo human apolipoprotein E isoform fractional turnover rates in the CNS.

    Directory of Open Access Journals (Sweden)

    Kristin R Wildsmith

    Full Text Available Apolipoprotein E (ApoE is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4 each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD. Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS, we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.

  4. Nanomaterials for delivery of nucleic acid to the central nervous system (CNS)

    DEFF Research Database (Denmark)

    Wang, Danyang; Wu, Lin-Ping

    2017-01-01

    -related disease, such as neurodegeneration and disorders, suitable, safe and effective drug delivery nanocarriers have to been developed to overcome the blood brain barrier (BBB), which is the most inflexible barrier in human body. Here, we highlight the structure and function of barriers in the central nervous...... system (CNS) and summary several types of nanomaterials which can be potentially used in the brain delivery nucleic acid....

  5. MicroRNA (miRNA Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD-Novel and Unique Pathological Features

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    Yuhai Zhao

    2015-12-01

    Full Text Available Of the approximately ~2.65 × 103 mature microRNAs (miRNAs so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS. This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD and related forms of chronic neurodegeneration; and (ii highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS.

  6. MicroRNA (miRNA) Signaling in the Human CNS in Sporadic Alzheimer’s Disease (AD)-Novel and Unique Pathological Features

    Science.gov (United States)

    Zhao, Yuhai; Pogue, Aileen I.; Lukiw, Walter J.

    2015-01-01

    Of the approximately ~2.65 × 103 mature microRNAs (miRNAs) so far identified in Homo sapiens, only a surprisingly small but select subset—about 35–40—are highly abundant in the human central nervous system (CNS). This fact alone underscores the extremely high selection pressure for the human CNS to utilize only specific ribonucleotide sequences contained within these single-stranded non-coding RNAs (ncRNAs) for productive miRNA–mRNA interactions and the down-regulation of gene expression. In this article we will: (i) consolidate some of our still evolving ideas concerning the role of miRNAs in the CNS in normal aging and in health, and in sporadic Alzheimer’s disease (AD) and related forms of chronic neurodegeneration; and (ii) highlight certain aspects of the most current work in this research field, with particular emphasis on the findings from our lab of a small pathogenic family of six inducible, pro-inflammatory, NF-κB-regulated miRNAs including miRNA-7, miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155. This group of six CNS-abundant miRNAs significantly up-regulated in sporadic AD are emerging as what appear to be key mechanistic contributors to the sporadic AD process and can explain much of the neuropathology of this common, age-related inflammatory neurodegeneration of the human CNS. PMID:26694372

  7. Detail Design of the hydrogen system and the gas blanketing system for the HANARO-CNS

    International Nuclear Information System (INIS)

    Choi, Jung Woon; Kim, Hark Rho; Kim, Young Ki; Wu, Sang Ik; Kim, Bong Su; Lee, Yong Seop

    2007-04-01

    The cold neutron source (CNS), which will be installed in the vertical CN hole of the reflector tank at HANARO, makes thermal neutrons to moderate into the cold neutrons with the ranges of 0.1 ∼ 10 meV passing through a moderator at about 22K. A moderator to produce cold neutrons is liquid hydrogen, which liquefies by the heat transfer with cryogenic helium flowing from the helium refrigeration system (HRS). Because of its installed location, the hydrogen system is designed to be surrounded by the gas blanketing system to notify the leakage on the system and to prevent hydrogen leakage out of the CNS. The hydrogen system, consisted of hydrogen charging unit, hydrogen storage unit, hydrogen buffer tank, and hydrogen piping, is designed to smoothly and safely supply hydrogen to and to draw back hydrogen from the IPA of the CNS under the HRS operation mode. Described is that calculation for total required hydrogen amount in the CNS as well as operation schemes of the hydrogen system. The gas blanketing system (GBS) is designed for the supply of the compressed nitrogen gas into the air pressurized valves for the CNS, to isolate the hydrogen system from the air and the water, and to prevent air or water intrusion into the vacuum system as well as the hydrogen system. All detail descriptions are shown inhere as well as the operation scheme for the GBS

  8. Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions

    DEFF Research Database (Denmark)

    Kuhlmann, Tanja; Remington, Leah; Maruschak, Brigitte

    2007-01-01

    to be strongly expressed in mature oligodendrocytes in vivo. In the present investigation we analyzed the expression patterns of Nogo-A in adult mouse and human CNS as well as in demyelinating animal models and multiple sclerosis lesions. Nogo-A expression was compared with that of other frequently used...... oligodendroglial markers such as CC1, CNP, and in situ hybridization for proteolipid protein mRNA. Nogo-A strongly and reliably labeled oligodendrocytes in the adult CNS as well as in demyelinating lesions and thus represents a valuable tool for the identification of oligodendrocytes in human and mouse CNS tissue...

  9. VIIP: Central Nervous System (CNS) Modeling

    Science.gov (United States)

    Vera, Jerry; Mulugeta, Lealem; Nelson, Emily; Raykin, Julia; Feola, Andrew; Gleason, Rudy; Samuels, Brian; Ethier, C. Ross; Myers, Jerry

    2015-01-01

    Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome. It has been hypothesized that the headward shift of cerebrospinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn may then induce VIIP syndrome through interaction with various biomechanical pathways. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the related IWS works submitted by Nelson et al., Feola et al. and Ethier et al.

  10. Targeted CNS delivery using human MiniPromoters and demonstrated compatibility with adeno-associated viral vectors

    Directory of Open Access Journals (Sweden)

    Charles N de Leeuw

    2014-01-01

    Full Text Available Critical for human gene therapy is the availability of small promoters tools to drive gene expression in a highly specific and reproducible manner. We tackled this challenge by developing human DNA MiniPromoters (MiniPs using computational biology and phylogenetic conservation. MiniPs were tested in mouse as single-copy knock-ins at the Hprt locus on the X chromosome and evaluated for lacZ reporter expression in central nervous system (CNS and non–CNS tissue. Eighteen novel MiniPs driving expression in mouse brain were identified, 2 MiniPs for driving pan-neuronal expression and 17 MiniPs for the mouse eye. Key areas of therapeutic interest were represented in this set: the cerebral cortex, embryonic hypothalamus, spinal cord, bipolar and ganglion cells of the retina, and skeletal muscle. We also demonstrated that three retinal ganglion cell MiniPs exhibit similar cell type specificity when delivered via adeno-associated virus vectors intravitreally. We conclude that our methodology and characterization has resulted in desirable expression characteristics that are intrinsic to the MiniPromoter, not dictated by copy-number effects or genomic location, and results in constructs predisposed to success in adeno-associated virus. These MiniPs are immediately applicable for preclinical studies toward gene therapy in humans and are publicly available to facilitate basic and clinical research, and human gene therapy.

  11. PEG minocycline-liposomes ameliorate CNS autoimmune disease.

    Directory of Open Access Journals (Sweden)

    Wei Hu

    Full Text Available Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS. Minocycline, a potent inhibitor of matrix metalloproteinase (MMP-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS. Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG minocycline liposomes are effective in treating EAE.Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs, we determined that PEG minocycline-liposome preparations stabilized with CaCl(2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number.Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.

  12. Microtubule-Targeting Agents Enter the Central Nervous System (CNS): Double-edged Swords for Treating CNS Injury and Disease.

    Science.gov (United States)

    Hur, Eun-Mi; Lee, Byoung Dae

    2014-12-01

    Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs) are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS) are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.

  13. Microtubule-Targeting Agents Enter the Central Nervous System (CNS: Double-edged Swords for Treating CNS Injury and Disease

    Directory of Open Access Journals (Sweden)

    Eun-Mi Hur

    2014-12-01

    Full Text Available Microtubules have been among the most successful targets in anticancer therapy and a large number of microtubule-targeting agents (MTAs are in various stages of clinical development for the treatment of several malignancies. Given that injury and diseases in the central nervous system (CNS are accompanied by acute or chronic disruption of the structural integrity of neurons and that microtubules provide structural support for the nervous system at cellular and intracellular levels, microtubules are emerging as potential therapeutic targets for treating CNS disorders. It has been postulated that exogenous application of MTAs might prevent the breakdown or degradation of microtubules after injury or during neurodegeneration, which will thereby aid in preserving the structural integrity and function of the nervous system. Here we review recent evidence that supports this notion and also discuss potential risks of targeting microtubules as a therapy for treating nerve injury and neurodegenerative diseases.

  14. CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?

    Science.gov (United States)

    Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

    2009-12-01

    While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

  15. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    Energy Technology Data Exchange (ETDEWEB)

    Vuillemenot, Brian R., E-mail: bvuillemenot@bmrn.com [BioMarin Pharmaceutical Inc., Novato, CA (United States); Kennedy, Derek [BioMarin Pharmaceutical Inc., Novato, CA (United States); Reed, Randall P.; Boyd, Robert B. [Northern Biomedical Research, Inc., Muskegon, MI (United States); Butt, Mark T. [Tox Path Specialists, LLC, Hagerstown, MD (United States); Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O' Neill, Charles A. [BioMarin Pharmaceutical Inc., Novato, CA (United States)

    2014-05-15

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  16. Recombinant human tripeptidyl peptidase-1 infusion to the monkey CNS: Safety, pharmacokinetics, and distribution

    International Nuclear Information System (INIS)

    Vuillemenot, Brian R.; Kennedy, Derek; Reed, Randall P.; Boyd, Robert B.; Butt, Mark T.; Musson, Donald G.; Keve, Steve; Cahayag, Rhea; Tsuruda, Laurie S.; O'Neill, Charles A.

    2014-01-01

    CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20 mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3–14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS. - Highlights: • TPP1 enzyme replacement therapy to the CNS is in development for CLN2 disease. • Toxicology, pharmacokinetics, and CNS distribution were assessed in monkeys. • TPP1 infusion directly to the brain did not result in any safety concerns. • A positive pharmacokinetic and distribution profile resulted from TPP1 infusion. • This study demonstrates the feasibility of ICV administered

  17. A safety assessment methodology applied to CNS/ATM-based air traffic control system

    Energy Technology Data Exchange (ETDEWEB)

    Vismari, Lucio Flavio, E-mail: lucio.vismari@usp.b [Safety Analysis Group (GAS), School of Engineering at University of Sao Paulo (Poli-USP), Av. Prof. Luciano Gualberto, Trav.3, n.158, Predio da Engenharia de Eletricidade, Sala C2-32, CEP 05508-900, Sao Paulo (Brazil); Batista Camargo Junior, Joao, E-mail: joaocamargo@usp.b [Safety Analysis Group (GAS), School of Engineering at University of Sao Paulo (Poli-USP), Av. Prof. Luciano Gualberto, Trav.3, n.158, Predio da Engenharia de Eletricidade, Sala C2-32, CEP 05508-900, Sao Paulo (Brazil)

    2011-07-15

    In the last decades, the air traffic system has been changing to adapt itself to new social demands, mainly the safe growth of worldwide traffic capacity. Those changes are ruled by the Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) paradigm , based on digital communication technologies (mainly satellites) as a way of improving communication, surveillance, navigation and air traffic management services. However, CNS/ATM poses new challenges and needs, mainly related to the safety assessment process. In face of these new challenges, and considering the main characteristics of the CNS/ATM, a methodology is proposed at this work by combining 'absolute' and 'relative' safety assessment methods adopted by the International Civil Aviation Organization (ICAO) in ICAO Doc.9689 , using Fluid Stochastic Petri Nets (FSPN) as the modeling formalism, and compares the safety metrics estimated from the simulation of both the proposed (in analysis) and the legacy system models. To demonstrate its usefulness, the proposed methodology was applied to the 'Automatic Dependent Surveillance-Broadcasting' (ADS-B) based air traffic control system. As conclusions, the proposed methodology assured to assess CNS/ATM system safety properties, in which FSPN formalism provides important modeling capabilities, and discrete event simulation allowing the estimation of the desired safety metric.

  18. A safety assessment methodology applied to CNS/ATM-based air traffic control system

    International Nuclear Information System (INIS)

    Vismari, Lucio Flavio; Batista Camargo Junior, Joao

    2011-01-01

    In the last decades, the air traffic system has been changing to adapt itself to new social demands, mainly the safe growth of worldwide traffic capacity. Those changes are ruled by the Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) paradigm , based on digital communication technologies (mainly satellites) as a way of improving communication, surveillance, navigation and air traffic management services. However, CNS/ATM poses new challenges and needs, mainly related to the safety assessment process. In face of these new challenges, and considering the main characteristics of the CNS/ATM, a methodology is proposed at this work by combining 'absolute' and 'relative' safety assessment methods adopted by the International Civil Aviation Organization (ICAO) in ICAO Doc.9689 , using Fluid Stochastic Petri Nets (FSPN) as the modeling formalism, and compares the safety metrics estimated from the simulation of both the proposed (in analysis) and the legacy system models. To demonstrate its usefulness, the proposed methodology was applied to the 'Automatic Dependent Surveillance-Broadcasting' (ADS-B) based air traffic control system. As conclusions, the proposed methodology assured to assess CNS/ATM system safety properties, in which FSPN formalism provides important modeling capabilities, and discrete event simulation allowing the estimation of the desired safety metric.

  19. Immune regulation and CNS autoimmune disease

    DEFF Research Database (Denmark)

    Antel, J P; Owens, T

    1999-01-01

    The central nervous system is a demonstrated target of both clinical and experimental immune mediated disorders. Immune regulatory mechanisms operative at the levels of the systemic immune system, the blood brain barrier, and within the CNS parenchyma are important determinants of the intensity...... and duration of the tissue directed injury. Convergence of research, involving direct manipulation of specific cells and molecular mediators in animal models and in vitro analysis of human immune and neural cells and tissues, is providing increasing insight into the role of these immune regulatory functions...

  20. Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways

    Directory of Open Access Journals (Sweden)

    Elkington Paul T

    2011-05-01

    Full Text Available Abstract Tuberculosis (TB of the central nervous system (CNS is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2 which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb, but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.

  1. Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics.

    Science.gov (United States)

    de Lange, Elizabeth C M; van den Brink, Willem; Yamamoto, Yumi; de Witte, Wilhelmus E A; Wong, Yin Cheong

    2017-12-01

    CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time- and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentration-time profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans.

  2. Reorganization of the human central nervous system.

    Science.gov (United States)

    Schalow, G; Zäch, G A

    2000-10-01

    The key strategies on which the discovery of the functional organization of the central nervous system (CNS) under physiologic and pathophysiologic conditions have been based included (1) our measurements of phase and frequency coordination between the firings of alpha- and gamma-motoneurons and secondary muscle spindle afferents in the human spinal cord, (2) knowledge on CNS reorganization derived upon the improvement of the functions of the lesioned CNS in our patients in the short-term memory and the long-term memory (reorganization), and (3) the dynamic pattern approach for re-learning rhythmic coordinated behavior. The theory of self-organization and pattern formation in nonequilibrium systems is explicitly related to our measurements of the natural firing patterns of sets of identified single neurons in the human spinal premotor network and re-learned coordinated movements following spinal cord and brain lesions. Therapy induced cell proliferation, and maybe, neurogenesis seem to contribute to the host of structural changes during the process of re-learning of the lesioned CNS. So far, coordinated functions like movements could substantially be improved in every of the more than 100 patients with a CNS lesion by applying coordination dynamic therapy. As suggested by the data of our patients on re-learning, the human CNS seems to have a second integrative strategy for learning, re-learning, storing and recalling, which makes an essential contribution of the functional plasticity following a CNS lesion. A method has been developed by us for the simultaneous recording with wire electrodes of extracellular action potentials from single human afferent and efferent nerve fibres of undamaged sacral nerve roots. A classification scheme of the nerve fibres in the human peripheral nervous system (PNS) could be set up in which the individual classes of nerve fibres are characterized by group conduction velocities and group nerve fibre diameters. Natural impulse patterns

  3. Human CNS cultures exposed to HIV-1 gp120 reproduce dendritic injuries of HIV-1-associated dementia

    Directory of Open Access Journals (Sweden)

    Hammond Robert R

    2004-05-01

    Full Text Available Abstract HIV-1-associated dementia remains a common subacute to chronic central nervous system degeneration in adult and pediatric HIV-1 infected populations. A number of viral and host factors have been implicated including the HIV-1 120 kDa envelope glycoprotein (gp120. In human post-mortem studies using confocal scanning laser microscopy for microtubule-associated protein 2 and synaptophysin, neuronal dendritic pathology correlated with dementia. In the present study, primary human CNS cultures exposed to HIV-1 gp120 at 4 weeks in vitro suffered gliosis and dendritic damage analogous to that described in association with HIV-1-associated dementia.

  4. Neuroprotective effects of estrogen in CNS injuries: insights from animal models

    Directory of Open Access Journals (Sweden)

    Raghava N

    2017-07-01

    Full Text Available Narayan Raghava,1 Bhaskar C Das,2 Swapan K Ray1 1Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Abstract: Among the estrogens that are biosynthesized in the human body, 17β-estradiol (estradiol or E2 is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS injuries such as spinal cord injury (SCI, traumatic brain injury (TBI, and ischemic brain injury (IBI. These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for

  5. Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS).

    Science.gov (United States)

    Krause, Sarah; Pfeiffer, Christian; Strube, Susanne; Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Loges, Sonja; Waizenegger, Jonas; Ben-Batalla, Isabel; Cario, Gunnar; Möricke, Anja; Stanulla, Martin; Schrappe, Martin; Schewe, Denis M

    2015-01-29

    Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target. © 2015 by The American Society of Hematology.

  6. A Novel Robust H∞ Filter Based on Krein Space Theory in the SINS/CNS Attitude Reference System

    Directory of Open Access Journals (Sweden)

    Fei Yu

    2016-03-01

    Full Text Available Owing to their numerous merits, such as compact, autonomous and independence, the strapdown inertial navigation system (SINS and celestial navigation system (CNS can be used in marine applications. What is more, due to the complementary navigation information obtained from two different kinds of sensors, the accuracy of the SINS/CNS integrated navigation system can be enhanced availably. Thus, the SINS/CNS system is widely used in the marine navigation field. However, the CNS is easily interfered with by the surroundings, which will lead to the output being discontinuous. Thus, the uncertainty problem caused by the lost measurement will reduce the system accuracy. In this paper, a robust H∞ filter based on the Krein space theory is proposed. The Krein space theory is introduced firstly, and then, the linear state and observation models of the SINS/CNS integrated navigation system are established reasonably. By taking the uncertainty problem into account, in this paper, a new robust H∞ filter is proposed to improve the robustness of the integrated system. At last, this new robust filter based on the Krein space theory is estimated by numerical simulations and actual experiments. Additionally, the simulation and experiment results and analysis show that the attitude errors can be reduced by utilizing the proposed robust filter effectively when the measurements are missing discontinuous. Compared to the traditional Kalman filter (KF method, the accuracy of the SINS/CNS integrated system is improved, verifying the robustness and the availability of the proposed robust H∞ filter.

  7. Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development.

    Directory of Open Access Journals (Sweden)

    Kate Kosmac

    2013-03-01

    Full Text Available Infection of the developing fetus with human cytomegalovirus (HCMV is a major cause of central nervous system disease in infants and children; however, mechanism(s of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.

  8. Human abuse liability evaluation of CNS stimulant drugs.

    Science.gov (United States)

    Romach, Myroslava K; Schoedel, Kerri A; Sellers, Edward M

    2014-12-01

    Psychoactive drugs that increase alertness, attention and concentration and energy, while also elevating mood, heart rate and blood pressure are referred to as stimulants. Despite some overlapping similarities, stimulants cannot be easily categorized by their chemical structure, mechanism of action, receptor binding profile, effects on monoamine uptake, behavioral pharmacology (e.g., effects on locomotion, temperature, and blood pressure), therapeutic indication or efficacy. Because of their abuse liability, a pre-market assessment of abuse potential is required for drugs that show stimulant properties; this review article focuses on the clinical aspects of this evaluation. This includes clinical trial adverse events, evidence of diversion or tampering, overdoses and the results of a human abuse potential study. While there are different types of human experimental studies that can be employed to evaluate stimulant abuse potential (e.g., drug discrimination, self-administration), only the human abuse potential study and clinical trial adverse event data are required for drug approval. The principal advances that have improved human abuse potential studies include using study enrichment strategies (pharmacologic qualification), larger sample sizes, better selection of endpoints and measurement strategies and more carefully considered interpretation of data. Because of the methodological advances, comparisons of newer studies with historical data is problematic and may contribute to a biased regulatory framework for the evaluation of newer stimulant-like drugs, such as A2 antagonists. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Molecular stress response in the CNS of mice after systemic exposureto interferon-alpha, ionizing radiation and ketamine

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, Xiu R.; Marchetti, Francesco; Lu, Xiaochen; Wyrobek, Andrew J.

    2009-03-03

    We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adultmice 30 min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4 h after systemic exposure to interferon-a (IFN-a) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-a (a single i.p. injection at 1 x 105 IU/kg) or whole body gamma-radiation (10 cGy or 2 Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-a, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10 cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-a treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex andhippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

  10. microRNAs in CNS disorders

    DEFF Research Database (Denmark)

    Kocerha, Jannet; Kauppinen, Sakari; Wahlestedt, Claes

    2009-01-01

    RNAs (miRNAs) have been identified in the mammalian central nervous system (CNS) and are reported to mediate pivotal roles in many aspects of neuronal functions. Disruption of miRNA-based post-transcriptional regulation has been implicated in a range of CNS disorders as one miRNA is predicted to impact...

  11. Installation and Commissioning of the Helium Refrigeration System for the HANARO-CNS

    International Nuclear Information System (INIS)

    Choi, Jung Woon; Kim, Young Ki; Wu, Sang Ik; Son, Woo Jung

    2009-11-01

    The cold neutron source (CNS), which will be installed in the vertical CN hole of the reflector tank at HANARO, makes thermal neutrons to moderate into the cold neutrons with the ranges of 0.1 ∼ 10 meV passing through a moderator at about 22K. A moderator to produce cold neutrons is liquid hydrogen, which liquefies by the heat transfer with cryogenic helium flowing from the helium refrigeration system. For the maintenance of liquid hydrogen in the IPA, the CNS system is mainly consisted of the hydrogen system to supply the hydrogen to the IPA, the vacuum system to keep the cryogenic liquid hydrogen in the IPA, and the helium refrigeration system to liquefy the hydrogen gas. The helium refrigeration system can be divided into two sections: one is the helium compression part from the low pressure gas to the high pressure gas and the other is the helium expansion part from the high temperature gas and pressure to low temperature and pressure gas by the expansion turbine. The helium refrigeration system except the warm helium pipe and the helium buffer tank has been manufactured by Linde Kryotechnik, AG in Switzerland and installed in the research reactor hall, HANARO. Other components have been manufactured in the domestic company. This technical report deals with the issues, its solutions, and other particular points while the helium refrigeration system was installed at site, verified its performance, and conducted its commissioning along the reactor operation. Furthermore, the operation procedure of the helium refrigeration system is included in here for the normal operation of the CNS

  12. CNS Damage Classification in Newborn Infants by Neural Network Based Cry Analysis

    NARCIS (Netherlands)

    Poel, Mannes; Ekkel, T.

    2002-01-01

    The central nervous system (CNS) of the human body is the whole system of brain, spinal marrow and nerve cells throughout the body that correlates and regulates the internal reactions of the body and controls its adjustment to the environment. It controls muscles and processes sensory information

  13. Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia.

    Science.gov (United States)

    Zheng, Changcheng; Liu, Xin; Zhu, Weibo; Cai, Xiaoyan; Wu, Jingsheng; Sun, Zimin

    2014-06-01

    The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P adult AML, but further studies are needed to improve the long-term survival.

  14. SINS/CNS Nonlinear Integrated Navigation Algorithm for Hypersonic Vehicle

    Directory of Open Access Journals (Sweden)

    Yong-jun Yu

    2015-01-01

    Full Text Available Celestial Navigation System (CNS has characteristics of accurate orientation and strong autonomy and has been widely used in Hypersonic Vehicle. Since the CNS location and orientation mainly depend upon the inertial reference that contains errors caused by gyro drifts and other error factors, traditional Strap-down Inertial Navigation System (SINS/CNS positioning algorithm setting the position error between SINS and CNS as measurement is not effective. The model of altitude azimuth, platform error angles, and horizontal position is designed, and the SINS/CNS tightly integrated algorithm is designed, in which CNS altitude azimuth is set as measurement information. GPF (Gaussian particle filter is introduced to solve the problem of nonlinear filtering. The results of simulation show that the precision of SINS/CNS algorithm which reaches 130 m using three stars is improved effectively.

  15. Applications of Genomic Sequencing in Pediatric CNS Tumors.

    Science.gov (United States)

    Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

    2016-05-01

    Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

  16. Nanomedicines for the Treatment of CNS Diseases.

    Science.gov (United States)

    Reynolds, Jessica L; Mahato, Ram I

    2017-03-01

    Targeting and delivering macromolecular therapeutics to the central nervous system (CNS) has been a major challenge. The blood-brain barrier (BBB) is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Therefore, much effort has been channelled into improving transport of therapeutics across the BBB and into the CNS including the use of nanoparticles. In this thematic issue, several reviews and original research are presented that address "Nanomedicines for CNS Diseases." The articles in this issue are concentrated on either CNS-HIV disease or CNS tumors. In regards to CNS-HIV disease, there are two reviews that discuss the role of nanoparticles for improving the delivery of HIV therapeutics to the CNS. In addition, there are two original articles focusing on therapies for CNS-HIV, one of them uses nanoparticles for delivery of siRNA specific to a key protein in autophagy to microglia, and another discusses nanoparticle delivery of a soluble mediator to suppress neuroinflammation. Furthermore, a comprehensive review about gene therapy for CNS neurological diseases is also included. Finally, this issue also includes review articles on enhanced drug targeting to CNS tumors. These articles include a review on the use of nanoparticles for CNS tumors, a review on functionalization (ligands) of nanoparticles for drug targeting to the brain tumor by overcoming BBB, and the final review discusses the use of macrophages as a delivery vehicle to CNS tumors. This thematic issue provides a wealth of knowledge on using nanomedicines for CNS diseases.

  17. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

    OpenAIRE

    2008-01-01

    Abstract Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m2 of MTX (4 h infu...

  18. Pathological classification of human iPSC-derived neural stem/progenitor cells towards safety assessment of transplantation therapy for CNS diseases.

    Science.gov (United States)

    Sugai, Keiko; Fukuzawa, Ryuji; Shofuda, Tomoko; Fukusumi, Hayato; Kawabata, Soya; Nishiyama, Yuichiro; Higuchi, Yuichiro; Kawai, Kenji; Isoda, Miho; Kanematsu, Daisuke; Hashimoto-Tamaoki, Tomoko; Kohyama, Jun; Iwanami, Akio; Suemizu, Hiroshi; Ikeda, Eiji; Matsumoto, Morio; Kanemura, Yonehiro; Nakamura, Masaya; Okano, Hideyuki

    2016-09-19

    The risk of tumorigenicity is a hurdle for regenerative medicine using induced pluripotent stem cells (iPSCs). Although teratoma formation is readily distinguishable, the malignant transformation of iPSC derivatives has not been clearly defined due to insufficient analysis of histology and phenotype. In the present study, we evaluated the histology of neural stem/progenitor cells (NSPCs) generated from integration-free human peripheral blood mononuclear cell (PBMC)-derived iPSCs (iPSC-NSPCs) following transplantation into central nervous system (CNS) of immunodeficient mice. We found that transplanted iPSC-NSPCs produced differentiation patterns resembling those in embryonic CNS development, and that the microenvironment of the final site of migration affected their maturational stage. Genomic instability of iPSCs correlated with increased proliferation of transplants, although no carcinogenesis was evident. The histological classifications presented here may provide cues for addressing potential safety issues confronting regenerative medicine involving iPSCs.

  19. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients

    Energy Technology Data Exchange (ETDEWEB)

    Offiah, C.E. [Department of Neuroradiology, Hope Hospital, Stott Lane, Salford, Manchester (United Kingdom)]. E-mail: chockycj@yahoo.co.uk; Turnbull, I.W. [Department of Neuroradiology, Hope Hospital, Stott Lane, Salford, Manchester (United Kingdom)

    2006-05-15

    The spectrum of pathology affecting the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome (AIDS) is broad and comprises predominantly opportunistic infections and neoplasms. It is estimated that approximately one-third of all patients with AIDS develop neurological complications. The organisms responsible for AIDS are human retroviruses: primarily the human immunodeficiency virus type 1 (HIV). In this review we shall focus on the neurological complications of HIV and AIDS which are applicable to the more frequently occurring intracranial infective organisms. Attention will be paid specifically to those CNS manifestations occurring in the adult HIV and AIDS population as infection in the paediatric HIV and AIDS group, although bearing some similarities, demonstrates some important differences.

  20. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients

    International Nuclear Information System (INIS)

    Offiah, C.E.; Turnbull, I.W.

    2006-01-01

    The spectrum of pathology affecting the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome (AIDS) is broad and comprises predominantly opportunistic infections and neoplasms. It is estimated that approximately one-third of all patients with AIDS develop neurological complications. The organisms responsible for AIDS are human retroviruses: primarily the human immunodeficiency virus type 1 (HIV). In this review we shall focus on the neurological complications of HIV and AIDS which are applicable to the more frequently occurring intracranial infective organisms. Attention will be paid specifically to those CNS manifestations occurring in the adult HIV and AIDS population as infection in the paediatric HIV and AIDS group, although bearing some similarities, demonstrates some important differences

  1. The glymphatic system in CNS health and disease: past, present and future

    Science.gov (United States)

    Plog, Benjamin A.; Nedergaard, Maiken

    2018-01-01

    The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here we review the role of the glymphatic pathway in CNS physiology, factors known to regulate glymphatic flow, and pathologic processes where a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, will also be discussed. PMID:29195051

  2. Heterogeneity of D-Serine Distribution in the Human Central Nervous System

    Science.gov (United States)

    Suzuki, Masataka; Imanishi, Nobuaki; Mita, Masashi; Hamase, Kenji; Aiso, Sadakazu

    2017-01-01

    D-serine is an endogenous ligand for N-methyl-D-aspartate glutamate receptors. Accumulating evidence including genetic associations of D-serine metabolism with neurological or psychiatric diseases suggest that D-serine is crucial in human neurophysiology. However, distribution and regulation of D-serine in humans are not well understood. Here, we found that D-serine is heterogeneously distributed in the human central nervous system (CNS). The cerebrum contains the highest level of D-serine among the areas in the CNS. There is heterogeneity in its distribution in the cerebrum and even within the cerebral neocortex. The neocortical heterogeneity is associated with Brodmann or functional areas but is unrelated to basic patterns of cortical layer structure or regional expressional variation of metabolic enzymes for D-serine. Such D-serine distribution may reflect functional diversity of glutamatergic neurons in the human CNS, which may serve as a basis for clinical and pharmacological studies on D-serine modulation. PMID:28604057

  3. The development of [18F]cyclofoxy as a ligand for imaging opioid receptors in the CNS of conscious humans

    International Nuclear Information System (INIS)

    Rice, K.C.; Newman, A.H.; Ostrowski, N.L.; Cohen, R.M.; Pert, A.; Pert, C.B.; Burke, T.R. Jr.; McLellan, C.A.; Channing, M.A.; Finn, R.D.; Dunn, B.; Simpson, N.; Carson, R.W.; Larson, S.M.; Eckelman, W.C.; Bennett, J.M.; Kawai, R.; Sawada, Y.; Herscovitch, P.; Yolles, P.S.; Nordhal, T.; Gross, M.; Blasberg, R.

    1989-01-01

    Positron emission tomography (PET) is a unique, noninvasive technique applicable to real time visualization and quantitation of drug receptor occupancy in the brain of conscious humans. Such studies with the normal and abnormal human CNS can potentially provide insight into the biochemical basis of disease states and the effects of drug therapy. The (-)-enantiomer of cyclofoxy, a fluorinated, potent narcotic antagonist derived from naltrexone, has been developed at NIH as an agent for study of the opioid receptor-endorphin system using PET. The development and current status of this program is described, including application of the NIH Opiate Total Synthesis for production the pharmacologically inert (+)-[ 18 F]cyclofoxy required for quantitation of receptor occupancy

  4. Tendencies the treatment of the central nervous system (CNS) tumors

    International Nuclear Information System (INIS)

    Alert Silva, Jose; Jimenez Medina, Jose

    2004-01-01

    It is known that the treatment of the central nervous system (CNS) tumors is based on the use of surgery and radiotherapy (RT) and that chemotherapy (QMT) is used even more, as well as the other drugs. A bibliographic review was made to update the knowledge on the current trends and perspectives of RT applied to CNS tumors. The following were found among them: a) combinations of RT and CMT; b) radiosensitizers incorporated to the radiant treatment; c) angiogenesis inhibitors associated with RT; d) the scale-up or increase of the RT doses thanks to the development of new technologies, such as 3 D conformal radiotherapy, intensity- modulated radiotherapy, surgery and others. Another field of research is that of the changes in the rhythm or fractioning of the RT: hyperfractionated, accelerated, combinations of both, etc., which will allow mainly to increase the dosage scale-up

  5. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

    Al-Qadi, Sonia; Schiøtt, Morten; Hansen, Steen Honoré

    2015-01-01

    BACKGROUND: ABC efflux transporters at the blood brain barrier (BBB), namely the P-glycoprotein (P-gp), restrain the development of central nervous system (CNS) drugs. Consequently, early screening of CNS drug candidates is pivotal to identify those affected by efflux activity. Therefore, simple,...... barriers. CONCLUSION: Findings suggest a conserved mechanism of brain efflux activity between insects and vertebrates, confirming that this model holds promise for inexpensive and high-throughput screening relative to in vivo models, for CNS drug discovery....

  6. Supratentorial CNS malformations

    International Nuclear Information System (INIS)

    Zlatareva, D.

    2012-01-01

    Full text: Clinical suspicion of a developmental anomaly of the central nervous system (CNS) is a frequent indication for performing and magnetic resonance imaging (MRI) examination of the brain. Classification systems for malformation of the CNS are constantly revised according to newer scientific research. Developmental abnormalities can be classified in two main types. The first category consists of disorders of organogenesis in which genetic defects or any ischemic, metabolic, toxic or infectious insult to the developing brain can cause malformation. These malformations result from abnormal neuronal and glial proliferation and from anomalies of neuronal migration and or cortical organization. They are divided into supra- and infratentorial and may involve grey or white matter or both. The second category of congenital brain abnormalities is disorders of histogenesis which result from abnormal cell differentiation with a relatively normal brain appearance. Supratentorial CNS malformations could be divided into anomalies in telencephalic commissure, holoprosencephalies and malformations in cortical development. There are three main telencephalic commissures: the anterior commissure, the hippocampal commissure and the corpus callosum. Their morphology (hypoplasia, hyperplasia, agenesis, dysgenesis, even atrophy) reflects the development of the brain. Their agenesis, complete or partial, is one of the most commonly observed features in the malformations of the brain and is a part of many syndromes. Malformations of cortical development (MCD) are heterogeneous group of disease which result from disruption of 3 main stages of cortical development. The common clinical presentation is refractory epilepsy and or developmental delay. The most common MCD are heterotopias, focal cortical dysplasia, polymicrogyria, schizencephaly, pachygyria and lizencephaly. The exact knowledge of the brain anatomy and embryology is mandatory to provide a better apprehension of the

  7. Air pollution: mechanisms of neuroinflammation and CNS disease.

    Science.gov (United States)

    Block, Michelle L; Calderón-Garcidueñas, Lilian

    2009-09-01

    Air pollution has been implicated as a chronic source of neuroinflammation and reactive oxygen species (ROS) that produce neuropathology and central nervous system (CNS) disease. Stroke incidence and Alzheimer's and Parkinson's disease pathology are linked to air pollution. Recent reports reveal that air pollution components reach the brain; systemic effects that impact lung and cardiovascular disease also impinge upon CNS health. While mechanisms driving air pollution-induced CNS pathology are poorly understood, new evidence suggests that microglial activation and changes in the blood-brain barrier are key components. Here we summarize recent findings detailing the mechanisms through which air pollution reaches the brain and activates the resident innate immune response to become a chronic source of pro-inflammatory factors and ROS, culminating in CNS disease.

  8. Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial

    DEFF Research Database (Denmark)

    Pestalozzi, B.C.; Francis, P.; Quinaux, E.

    2008-01-01

    BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG...

  9. Mechanisms of CNS invasion and damage by parasites.

    Science.gov (United States)

    Kristensson, Krister; Masocha, Willias; Bentivoglio, Marina

    2013-01-01

    Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

    Science.gov (United States)

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J; Balasubramanian, Gnanaprakash; Worst, Barbara C; Pajtler, Kristian W; Brabetz, Sebastian; Johann, Pascal D; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M; Remke, Marc; Phillips, Joanna J; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C; Schniederjan, Matthew J; Santi, Mariarita; Buccoliero, Anna M; Dahiya, Sonika; Kramm, Christof M; von Bueren, André O; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S; Taylor, Michael D; Jones, Chris; Jabado, Nada; Karajannis, Matthias A; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M; Ellison, David W; Korshunov, Andrey; Kool, Marcel

    2016-02-25

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. The glymphatic system in CNS health and disease: past, present and future

    OpenAIRE

    Plog, Benjamin A.; Nedergaard, Maiken

    2018-01-01

    The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and th...

  12. CNS-directed gene therapy for lysosomal storage diseases

    OpenAIRE

    Sands, Mark S; Haskins, Mark E

    2008-01-01

    Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders usually caused by deficient activity of a single lysosomal enzyme. As most lysosomal enzymes are ubiquitously expressed, a deficiency in a single enzyme can affect multiple organ systems, including the central nervous system (CNS). At least 75% of all LSDs have a significant CNS component. Approaches such as bone marrow transplantation (BMT) or enzyme replacement therapy (ERT) can effectively treat the systemic dis...

  13. Causes of CNS inflammation and potential targets for anticonvulsants.

    Science.gov (United States)

    Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

    2013-08-01

    Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

  14. Innate Interferons Regulate CNS Inflammation

    DEFF Research Database (Denmark)

    Dieu, Ruthe; Khorooshi, Reza M. H.; Mariboe, Anne

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently...... potential IFN-inducing receptor that signals through NF-kB. Receptor activator of NF-kB (RANK) belongs to the TNF-receptor superfamily and has been shown to induce IFN-beta in medullary thymic epithelial cells affecting autoimmune regulatory processes and osteoclast precursor cells in association to bone...

  15. CNS role evolution.

    Science.gov (United States)

    Payne, J L; Baumgartner, R G

    1996-01-01

    THE CNS ROLE has been actualized in a variety of ways. Flexibility-inherent in the role-and the revolution in health care consciousness tend to place the CNS at risk for criticism regarding value to the organization. At Vanderbilt University Medical Center, a CNS task force evaluated the current reality of CNS practice and recommended role changes to include the financial analysis of patient care. After incorporating a financial perspective into our present practice, we have embarked on an interesting journey of post-Master's degree study, that of the tertiary care nurse practitioner. This practice option could elevated the clinical and financial aspects of providing cost-effective health care to a more autonomous role form; however, the transition has been challenging. Since 1990, the American Nurses Association has recommended that nursing school curricula change to meet the needs of the health care environment and provide increased career flexibility through creating one advanced degree incorporating both CNS and NP functions. Swiftly moving past differences and toward similarities will bridge the gap for advanced practice nurses in the future.

  16. Flavonoids and the CNS

    DEFF Research Database (Denmark)

    Jäger, Anna Katharina; Saaby, Lasse

    2011-01-01

    Flavonoids are present in almost all terrestrial plants, where they provide UV-protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure....... Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic ß-glucocidase. The absorbed aglycone is then conjugated by methylation......, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABA(A)-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine...

  17. Essentials and Perspectives of Computational Modelling Assistance for CNS-oriented Nanoparticle-based Drug Delivery Systems.

    Science.gov (United States)

    Kisała, Joanna; Heclik, Kinga I; Pogocki, Krzysztof; Pogocki, Dariusz

    2018-05-16

    The blood-brain barrier (BBB) is a complex system controlling two-way substances traffic between circulatory (cardiovascular) system and central nervous system (CNS). It is almost perfectly crafted to regulate brain homeostasis and to permit selective transport of molecules that are essential for brain function. For potential drug candidates, the CNS-oriented neuropharmaceuticals as well as for those of primary targets in the periphery, the extent to which a substance in the circulation gains access to the CNS seems crucial. With the advent of nanopharmacology the problem of the BBB permeability for drug nano-carriers gains new significance. Compare to some other fields of medicinal chemistry, the computational science of nanodelivery is still prematured to offer the black-box type solutions, especially for the BBB-case. However, even its enormous complexity can be spell out the physical principles, and as such subjected to computation. Basic understanding of various physico-chemical parameters describing the brain uptake is required to take advantage of their usage for the BBB-nanodelivery. This mini-review provides a sketchy introduction into essential concepts allowing application of computational simulation to the BBB-nanodelivery design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Maximum Correntropy Unscented Kalman Filter for Ballistic Missile Navigation System based on SINS/CNS Deeply Integrated Mode.

    Science.gov (United States)

    Hou, Bowen; He, Zhangming; Li, Dong; Zhou, Haiyin; Wang, Jiongqi

    2018-05-27

    Strap-down inertial navigation system/celestial navigation system ( SINS/CNS) integrated navigation is a high precision navigation technique for ballistic missiles. The traditional navigation method has a divergence in the position error. A deeply integrated mode for SINS/CNS navigation system is proposed to improve the navigation accuracy of ballistic missile. The deeply integrated navigation principle is described and the observability of the navigation system is analyzed. The nonlinearity, as well as the large outliers and the Gaussian mixture noises, often exists during the actual navigation process, leading to the divergence phenomenon of the navigation filter. The new nonlinear Kalman filter on the basis of the maximum correntropy theory and unscented transformation, named the maximum correntropy unscented Kalman filter, is deduced, and the computational complexity is analyzed. The unscented transformation is used for restricting the nonlinearity of the system equation, and the maximum correntropy theory is used to deal with the non-Gaussian noises. Finally, numerical simulation illustrates the superiority of the proposed filter compared with the traditional unscented Kalman filter. The comparison results show that the large outliers and the influence of non-Gaussian noises for SINS/CNS deeply integrated navigation is significantly reduced through the proposed filter.

  19. Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

    Directory of Open Access Journals (Sweden)

    Jacinta Nwamaka Nwogu

    2016-01-01

    Full Text Available Neurological complications associated with the human immunodeficiency virus (HIV are a matter of great concern. While antiretroviral (ARV drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

  20. Computerized tomography data on CNS affection in systemic lupus erythematosus

    International Nuclear Information System (INIS)

    Ivanova, M.M.; Bliznyuk, O.I.; Todua, F.I.; Tumanova, A.A.

    1989-01-01

    Computed tomography (CT) of the brain was employed in 40 patients with systemic lupus erythematosus (SLE). Clinical cerebral pathology was obvious in 30 and absent in 10 patients. By CT cerebral symptoms were divided of 4 groups. Clinical symptom complexes of CNS defects and SLE were reflected on definite CT images correlated with focal damage to the brain. CT picture of enlarged subarachnoid space, ventricles and basal cisterns can be observed in SLE patients without neurological symptoms. This indicated likely subclinical cerebral affection

  1. CNS embryonal tumours: WHO 2016 and beyond.

    Science.gov (United States)

    Pickles, J C; Hawkins, C; Pietsch, T; Jacques, T S

    2018-02-01

    Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies. © 2017 British Neuropathological Society.

  2. Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo

    International Nuclear Information System (INIS)

    Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.

    2006-01-01

    [ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site

  3. Electrophysiological CNS-processes related to associative learning in humans.

    Science.gov (United States)

    Christoffersen, Gert R J; Schachtman, Todd R

    2016-01-01

    The neurophysiology of human associative memory has been studied with electroencephalographic techniques since the 1930s. This research has revealed that different types of electrophysiological processes in the human brain can be modified by conditioning: sensory evoked potentials, sensory induced gamma-band activity, periods of frequency-specific waves (alpha and beta waves, the sensorimotor rhythm and the mu-rhythm) and slow cortical potentials. Conditioning of these processes has been studied in experiments that either use operant conditioning or repeated contingent pairings of conditioned and unconditioned stimuli (classical conditioning). In operant conditioning, the appearance of a specific brain process is paired with an external stimulus (neurofeedback) and the feedback enables subjects to obtain varying degrees of control of the CNS-process. Such acquired self-regulation of brain activity has found practical uses for instance in the amelioration of epileptic seizures, Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). It has also provided communicative means of assistance for tetraplegic patients through the use of brain computer interfaces. Both extra and intracortically recorded signals have been coupled with contingent external feedback. It is the aim for this review to summarize essential results on all types of electromagnetic brain processes that have been modified by classical or operant conditioning. The results are organized according to type of conditioned EEG-process, type of conditioning, and sensory modalities of the conditioning stimuli. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Neuromyelitis optica (NMO) - an autoimmune disease of the central nervous system (CNS)

    DEFF Research Database (Denmark)

    Asgari, N; Owens, T; Frøkiaer, J

    2010-01-01

    Asgari N, Owens T, Frøkiaer J, Stenager E, Lillevang ST, Kyvik KO. Neuromyelitis optica (NMO) - an autoimmune disease of the central nervous system (CNS).
Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01416.x.
© 2010 John Wiley & Sons A/S. In the past 10 years, neuromyelitis optica (NMO) has...... or by intrathecal administration to naive mice. NMO may be characterized as a channelopathy of the central nervous system with autoimmune characteristics....

  5. Role of resident CNS cell populations in HTLV-1-associated neuroinflammatory disease.

    Science.gov (United States)

    Lepoutre, Veronique; Jain, Pooja; Quann, Kevin; Wigdahl, Brian; Khan, Zafar K

    2009-01-01

    Human T cell leukemia virus type 1 (HTLV-1), the first human retrovirus discovered, is the etiologic agent for a number of disorders; the two most common pathologies include adult T cell leukemia (ATL) and a progressive demyelinating neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The neurologic dysfunction associated with HAM/TSP is a result of viral intrusion into the central nervous system (CNS) and the generation of a hyperstimulated host response within the peripheral and central nervous system that includes expanded populations of CD4+ and CD8+ T cells and proinflammatory cytokines/chemokines in the cerebrospinal fluid (CSF). This robust, yet detrimental immune response likely contributes to the death of myelin producing oligodendrocytes and degeneration of neuronal axons. The mechanisms of neurological degeneration in HAM/TSP have yet to be fully delineated in vivo and may involve the immunogenic properties of the HTLV-1 transactivator protein Tax. This comprehensive review characterizes the available knowledge to date concerning the effects of HTLV-1 on CNS resident cell populations with emphasis on both viral and host factors contributing to the genesis of HAM/TSP.

  6. Maximum Correntropy Unscented Kalman Filter for Ballistic Missile Navigation System based on SINS/CNS Deeply Integrated Mode

    Directory of Open Access Journals (Sweden)

    Bowen Hou

    2018-05-01

    Full Text Available Strap-down inertial navigation system/celestial navigation system ( SINS/CNS integrated navigation is a high precision navigation technique for ballistic missiles. The traditional navigation method has a divergence in the position error. A deeply integrated mode for SINS/CNS navigation system is proposed to improve the navigation accuracy of ballistic missile. The deeply integrated navigation principle is described and the observability of the navigation system is analyzed. The nonlinearity, as well as the large outliers and the Gaussian mixture noises, often exists during the actual navigation process, leading to the divergence phenomenon of the navigation filter. The new nonlinear Kalman filter on the basis of the maximum correntropy theory and unscented transformation, named the maximum correntropy unscented Kalman filter, is deduced, and the computational complexity is analyzed. The unscented transformation is used for restricting the nonlinearity of the system equation, and the maximum correntropy theory is used to deal with the non-Gaussian noises. Finally, numerical simulation illustrates the superiority of the proposed filter compared with the traditional unscented Kalman filter. The comparison results show that the large outliers and the influence of non-Gaussian noises for SINS/CNS deeply integrated navigation is significantly reduced through the proposed filter.

  7. Conceptual design and feasibility test of two-phase hydrogen thermal siphon system of CNS in CARR

    International Nuclear Information System (INIS)

    Bi Qincheng; Chen Tingkuan; Feng Quanke; Du Shejiao; Li Xiaoming; Wei Liang

    2004-01-01

    Conceptual design of the hydrogen system of cold neutron source (CNS) in China Advanced Research Reactor (CARR) was proposed, and feasibility test was carried out. In order to determine the void fraction in neutron moderator, the circulation ability of the two-phase hydrogen thermal siphon system, and the structure of components of the CNS, the mockup test was performed using Freon-113 as working fluid. To obtain the modeling criterion so that the above experimental results can be applied to the design of CARR, the bubble rising velocities in different liquids were investigated to study the effects of physical properties such as density, viscosity and surface tension on bubble rising velocity, void fraction and circulation ability

  8. Isolated vasculitis of the CNS

    International Nuclear Information System (INIS)

    Block, F.; Reith, W.

    2000-01-01

    Vasculitis is a rare cause for disease of the CNS. The isolated vasculitis of the CNS is restricted to the CNS whereas other forms of vasculitis affect various organs including the CNS. Headache, encephalopathy, focal deficits and epileptic seizures are the major symptoms suggestive for vasculitis. One major criterion of the isolated vasculitis of the CNS is the lack of evidence for other vasculitis forms or for pathology of other organs. Angiography displays multifocal segmental stenosis of intracranial vessels. MRI demonstrates multiple lesions which in part show enhancement after gadolinium. A definite diagnosis can only be made on the grounds of biopsy from leptomeninges and parenchyma. Therapy consists of corticosteroids and cyclophosphamid. (orig.) [de

  9. A homologous form of human interleukin 16 is implicated in microglia recruitment following nervous system injury in leech Hirudo medicinalis.

    Science.gov (United States)

    Croq, Françoise; Vizioli, Jacopo; Tuzova, Marina; Tahtouh, Muriel; Sautiere, Pierre-Eric; Van Camp, Christelle; Salzet, Michel; Cruikshank, William W; Pestel, Joel; Lefebvre, Christophe

    2010-11-01

    In contrast to mammals, the medicinal leech Hirudo medicinalis can completely repair its central nervous system (CNS) after injury. This invertebrate model offers unique opportunities to study the molecular and cellular basis of the CNS repair processes. When the leech CNS is injured, microglial cells migrate and accumulate at the site of lesion, a phenomenon known to be essential for the usual sprouting of injured axons. In the present study, we demonstrate that a new molecule, designated HmIL-16, having functional homologies with human interleukin-16 (IL-16), has chemotactic activity on leech microglial cells as observed using a gradient of human IL-16. Preincubation of microglial cells either with an anti-human IL-16 antibody or with anti-HmIL-16 antibody significantly reduced microglia migration induced by leech-conditioned medium. Functional homology was demonstrated further by the ability of HmIL-16 to promote human CD4+ T cell migration which was inhibited by antibody against human IL-16, an IL-16 antagonist peptide or soluble CD4. Immunohistochemistry of leech CNS indicates that HmIL-16 protein present in the neurons is rapidly transported and stored along the axonal processes to promote the recruitment of microglial cells to the injured axons. To our knowledge, this is the first identification of a functional interleukin-16 homologue in invertebrate CNS. The ability of HmIL-16 to recruit microglial cells to sites of CNS injury suggests a role for HmIL-16 in the crosstalk between neurons and microglia in the leech CNS repair.

  10. Human Immune System Mice for the Study of Human Immunodeficiency Virus-Type 1 Infection of the Central Nervous System

    Science.gov (United States)

    Evering, Teresa H.; Tsuji, Moriya

    2018-01-01

    Immunodeficient mice transplanted with human cell populations or tissues, also known as human immune system (HIS) mice, have emerged as an important and versatile tool for the in vivo study of human immunodeficiency virus-type 1 (HIV-1) pathogenesis, treatment, and persistence in various biological compartments. Recent work in HIS mice has demonstrated their ability to recapitulate critical aspects of human immune responses to HIV-1 infection, and such studies have informed our knowledge of HIV-1 persistence and latency in the context of combination antiretroviral therapy. The central nervous system (CNS) is a unique, immunologically privileged compartment susceptible to HIV-1 infection, replication, and immune-mediated damage. The unique, neural, and glia-rich cellular composition of this compartment, as well as the important role of infiltrating cells of the myeloid lineage in HIV-1 seeding and replication makes its study of paramount importance, particularly in the context of HIV-1 cure research. Current work on the replication and persistence of HIV-1 in the CNS, as well as cells of the myeloid lineage thought to be important in HIV-1 infection of this compartment, has been aided by the expanded use of these HIS mouse models. In this review, we describe the major HIS mouse models currently in use for the study of HIV-1 neuropathogenesis, recent insights from the field, limitations of the available models, and promising advances in HIS mouse model development. PMID:29670623

  11. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity.

    Science.gov (United States)

    Nogueiras, Ruben; Pérez-Tilve, Diego; Veyrat-Durebex, Christelle; Morgan, Donald A; Varela, Luis; Haynes, William G; Patterson, James T; Disse, Emmanuel; Pfluger, Paul T; López, Miguel; Woods, Stephen C; DiMarchi, Richard; Diéguez, Carlos; Rahmouni, Kamal; Rohner-Jeanrenaud, Françoise; Tschöp, Matthias H

    2009-05-06

    We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

  12. Optimization of dipeptidic inhibitors of cathepsin L for improved Toxoplasma gondii selectivity and CNS permeability.

    Science.gov (United States)

    Zwicker, Jeffery D; Diaz, Nicolas A; Guerra, Alfredo J; Kirchhoff, Paul D; Wen, Bo; Sun, Duxin; Carruthers, Vern B; Larsen, Scott D

    2018-06-01

    The neurotropic protozoan Toxoplasma gondii is the second leading cause of death due to foodborne illness in the US, and has been designated as one of five neglected parasitic infections by the Center for Disease Control and Prevention. Currently, no treatment options exist for the chronic dormant-phase Toxoplasma infection in the central nervous system (CNS). T. gondii cathepsin L (TgCPL) has recently been implicated as a novel viable target for the treatment of chronic toxoplasmosis. In this study, we report the first body of SAR work aimed at developing potent inhibitors of TgCPL with selectivity vs the human cathepsin L. Starting from a known inhibitor of human cathepsin L, and guided by structure-based design, we were able to modulate the selectivity for Toxoplasma vs human CPL by nearly 50-fold while modifying physiochemical properties to be more favorable for metabolic stability and CNS penetrance. The overall potency of our inhibitors towards TgCPL was improved from 2 μM to as low as 110 nM and we successfully demonstrated that an optimized analog 18b is capable of crossing the BBB (0.5 brain/plasma). This work is an important first step toward development of a CNS-penetrant probe to validate TgCPL as a feasible target for the treatment of chronic toxoplasmosis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Epstein-Barr virus and human herpesvirus type 8 infections of the central nervous system.

    Science.gov (United States)

    Volpi, Antonio

    2004-06-01

    In developing guidelines for the improved management of herpesvirus infections of the central nervous system (CNS), the International Herpes Management Forum (IHMF) has studied Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8)- related diseases. EBV has been associated with numerous CNS diseases including meningitis, encephalitis and post transplant lymphoproliferative disorder (PTLD). The pathogenesis of EBV-associated CNS disorders is not completely understood but may be due to direct virus invasion of the CNS. Alternatively, damage may be immunologically mediated by infiltration of cytotoxic CD8+ lymphocytes into neural tissue or deposition of antibody-antigen complexes. The IHMF recommends that diagnosis of EBV infections of the CNS may involve polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) for EBV DNA but the sensitivity and specificity of the technique remains to be determined. Furthermore, the value of PCR in this context may be limited as EBV DNA is often detected in patients without neurological symptoms. Antiviral therapy has not demonstrated clinical efficacy in the treatment of EBV-related CNS disorders. CNS complications of HHV-8 infection are rare, but the virus has been associated with AIDS-dementia complex, amyotrophic lateral sclerosis (ALS) and primary CNS lymphoma; however these links remain to be proven.

  14. Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.

    Directory of Open Access Journals (Sweden)

    Joseph L Mankowski

    Full Text Available Human immunodeficiency virus (HIV infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS disease using a well-characterized simian immunodeficiency (SIV/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5. Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001. Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.

  15. Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)

    2006-02-15

    [{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.

  16. When the Tail Can't Wag the Dog: The Implications of CNS-Intrinsic Initiation of Neuroinflammation

    Directory of Open Access Journals (Sweden)

    Deirdre S Davis

    2009-04-01

    Full Text Available The CNS (central nervous system is unquestionably the central organ that regulates directly or indirectly all physiological systems in the mammalian body. Yet, when considering the defence of the CNS from pathogens, the CNS has often been considered passive and subservient to the pro-inflammatory responses of the immune system. In this view, neuroinflammatory disorders are examples of when the tail (the immune system wags the dog (the CNS to the detriment of an individual's function and survival.

  17. CNS complications of rotavirus gastroenteritis

    International Nuclear Information System (INIS)

    Volosinova, D.

    2010-01-01

    Rotavirus infection may be accompanied by serious complications, e.g. disabilities central nervous system (CNS). Theory rotavirus penetration across the blood-brain barrier and subsequent rota-associated convulsions by the 2-year case-history of the patient. Rotavirosis minor gastrointestinal symptoms may lead to erroneous diagnosis. (author)

  18. Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: An International Primary CNS Lymphoma Collaborative Group report

    NARCIS (Netherlands)

    N.D. Doolittle (Nancy); L.E. Abrey (Lauren); T.N. Shenkier (Tamara); T. Siegal (Tali); J.E.C. Bromberg (Jacolien); E.A. Neuwelt (Edward); C. Soussain (Carole); K. Jahnke (Kristoph); P. Johnston (Patrick); G. Illerhaus (Gerald); D. Schiff (David); T.T. Batchelor (Tracy); S. Montoto (Silvia); D.F. Kraemer (Dale); E. Zucca (Emanuele)

    2008-01-01

    textabstractIsolated central nervous system (CNS) relapse involving the brain parenchyma is a rare complication of systemic non-Hodgkin lymphoma. We retrospectively analyzed patient characteristics, management, and outcomes of this complication. After complete response to initial non-Hodgkin

  19. Peroxisome Proliferator-Activated Receptors (PPARs as Potential Inducers of Antineoplastic Effects in CNS Tumors

    Directory of Open Access Journals (Sweden)

    Lars Tatenhorst

    2008-01-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS. The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.

  20. Immune Responses in the Central Nervous System Are Anatomically Segregated in a Non-Human Primate Model of Human Immunodeficiency Virus Infection

    Directory of Open Access Journals (Sweden)

    Barbara Tavano

    2017-03-01

    Full Text Available The human immunodeficiency virus (HIV accesses the central nervous system (CNS early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.

  1. Detection of transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics using a Drosophila systems model.

    Directory of Open Access Journals (Sweden)

    Abhay Sharma

    Full Text Available Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F(1 adults after treating F(0 adult males with PTZ and of F(2 adults resulting from a cross between F(1 males and normal females. Surprisingly, microarray clustering showed F(1 male profile as closest to F(1 female and F(0 male profile closest to F(2 male. Differentially expressed genes in F(1 males, F(1 females and F(2 males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F(2 males. Next, we generated microarray expression profiles of adult testis from F(0 and F(1 males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying

  2. Detection of transgenerational spermatogenic inheritance of adult male acquired CNS gene expression characteristics using a Drosophila systems model.

    Science.gov (United States)

    Sharma, Abhay; Singh, Priyanka

    2009-06-02

    Available instances of inheritance of epigenetic transgenerational phenotype are limited to environmental exposures during embryonic and adult gonadal development. Adult exposures can also affect gametogenesis and thereby potentially result in reprogramming of the germline. Although examples of epigenetic effects on gametogenesis exist, it is notable that transgenerational inheritance of environment-induced adult phenotype has not yet been reported. Epigenetic codes are considered to be critical in neural plasticity. A Drosophila systems model of pentylenetetrazole (PTZ) induced long-term brain plasticity has recently been described. In this model, chronic PTZ treatment of adult males causes alterations in CNS transcriptome. Here, we describe our search for transgenerational spermatogenic inheritance of PTZ induced gene expression phenotype acquired by adult Drosophila males. We generated CNS transcriptomic profiles of F(1) adults after treating F(0) adult males with PTZ and of F(2) adults resulting from a cross between F(1) males and normal females. Surprisingly, microarray clustering showed F(1) male profile as closest to F(1) female and F(0) male profile closest to F(2) male. Differentially expressed genes in F(1) males, F(1) females and F(2) males showed significant overlap with those caused by PTZ. Interestingly, microarray evidence also led to the identification of upregulated rRNA in F(2) males. Next, we generated microarray expression profiles of adult testis from F(0) and F(1) males. Further surprising, clustering of CNS and testis profiles and matching of differentially expressed genes in them provided evidence of a spermatogenic mechanism in the transgenerational effect observed. To our knowledge, we report for the first time detection of transgenerational spermatogenic inheritance of adult acquired somatic gene expression characteristic. The Drosophila systems model offers an excellent opportunity to understand the epigenetic mechanisms underlying the

  3. CNS Involvement in AML Patient Treated with 5-Azacytidine

    Directory of Open Access Journals (Sweden)

    Diamantina Vasilatou

    2014-01-01

    Full Text Available Central nervous system (CNS involvement in acute myeloid leukemia (AML is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status.

  4. Malignant lymphoma in central nervous system (CNS)

    International Nuclear Information System (INIS)

    Fujiyoshi, Kenji; Fukuyama, Hidenao; Akiguchi, Ichiro; Kameyama, Masakuni; Nishimura, Toshio.

    1984-01-01

    A 71-year-old male was admitted to Kohka Public Hospital on January 4, 1980, because of frequent vomiting and recent memory loss. Two weeks before admission upper G-I series showed no abnormalities. Physical and neurological examinations revealed no abnormalities except for slightly apathetic appearance and recent memory loss. Mild pleocytosis and marked increase of protein in CSF were observed. CT scan on January 17 showed high density areas in both medial sides of temporal lobes with remarkable contrast enhancement. His memory and, consciousness disturbances gradually aggravated, accompanied by abnormal density spreading around the ventricle walls like ventriculitis. He was transfered to Kyoto University Hospital on March 17, and malignant lymphoma was diagnosed on the basis of CSF cytology. Radiation and chemotherapy alleviated the CNS involvement and he regained normal mental function. On June 16, he developed pneumonia followed by status epilepticus. Autopsy findings revealed no lymphoid cell infiltration, but fibrous tissues in both hippocampal gyri and lymphomatous cells in the liver, which could not be suspected on clinical examinations. Apparent malignant lymphoma cells were not found in lymph nodes. This case indicated peculiar evolution of malignant lymphoma from liver to CNS or vice versa. We could not decide which organ was primary. CT findings of this case was very interesting; they resembled ventriculitis, which simulate tumors such as medulloblastoma or ependymoma spreading under ependymal lining. (author)

  5. Alcohol intake alters immune responses and promotes CNS viral persistence in mice.

    Science.gov (United States)

    Loftis, Jennifer M; Taylor, Jonathan; Raué, Hans-Peter; Slifka, Mark K; Huang, Elaine

    2016-10-01

    Chronic hepatitis C virus (HCV) infection leads to progressive liver disease and is associated with a variety of extrahepatic effects, including central nervous system (CNS) damage and neuropsychiatric impairments. Alcohol abuse can exacerbate these adverse effects on brain and behavior, but the molecular mechanisms are not well understood. This study investigated the role of alcohol in regulating viral persistence and CNS immunopathology in mice infected with lymphocytic choriomeningitis virus (LCMV), a model for HCV infections in humans. Female and male BALB/c mice (n=94) were exposed to alcohol (ethanol; EtOH) and water (or water only) using a two-bottle choice paradigm, followed one week later by infection with either LCMV clone 13 (causes chronic infection similar to chronic HCV), LCMV Armstrong (causes acute infection), or vehicle. Mice were monitored for 60days post-infection and continued to receive 24-h access to EtOH and water. Animals infected with LCMV clone 13 drank more EtOH, as compared to those with an acute or no viral infection. Six weeks after infection with LCMV clone 13, mice with EtOH exposure evidenced higher serum viral titers, as compared to mice without EtOH exposure. EtOH intake was also associated with reductions in virus-specific CD8(+) T cell frequencies (particularly CD11a(hi) subsets) and evidence of persistent CNS viremia in chronically infected mice. These findings support the hypothesis that EtOH use and chronic viral infection can result in combined toxic effects accelerating CNS damage and neuropsychiatric dysfunction and suggest that examining the role of EtOH in regulating viral persistence and CNS immunopathology in mice infected with LCMV can lead to a more comprehensive understanding of comorbid alcohol use disorder and chronic viral infection. Published by Elsevier B.V.

  6. Flavonoids and the CNS

    Directory of Open Access Journals (Sweden)

    Anna K. Jäger

    2011-02-01

    Full Text Available Flavonoids are present in almost all terrestrial plants, where they provide UV-protection and colour. Flavonoids have a fused ring system consisting of an aromatic ring and a benzopyran ring with a phenyl substituent. The flavonoids can be divided into several classes depending on their structure. Flavonoids are present in food and medicinal plants and are thus consumed by humans. They are found in plants as glycosides. Before oral absorption, flavonoids undergo deglycosylation either by lactase phloridzin hydrolase or cytosolic β-glucocidase. The absorbed aglycone is then conjugated by methylation, sulphatation or glucuronidation. Both the aglycones and the conjugates can pass the blood-brain barrier. In the CNS several flavones bind to the benzodiazepine site on the GABAA-receptor resulting in sedation, anxiolytic or anti-convulsive effects. Flavonoids of several classes are inhibitors of monoamine oxidase A or B, thereby working as anti-depressants or to improve the conditions of Parkinson’s patients. Flavanols, flavanones and anthocyanidins have protective effects preventing inflammatory processes leading to nerve injury. Flavonoids seem capable of influencing health and mood.

  7. In-motion initial alignment and positioning with INS/CNS/ODO integrated navigation system for lunar rovers

    Science.gov (United States)

    Lu, Jiazhen; Lei, Chaohua; Yang, Yanqiang; Liu, Ming

    2017-06-01

    Many countries have been paying great attention to space exploration, especially about the Moon and the Mars. Autonomous and high-accuracy navigation systems are needed for probers and rovers to accomplish missions. Inertial navigation system (INS)/celestial navigation system (CNS) based navigation system has been used widely on the lunar rovers. Initialization is a particularly important step for navigation. This paper presents an in-motion alignment and positioning method for lunar rovers by INS/CNS/odometer integrated navigation. The method can estimate not only the position and attitude errors, but also the biases of the accelerometers and gyros using the standard Kalman filter. The differences between the platform star azimuth, elevation angles and the computed star azimuth, elevation angles, and the difference between the velocity measured by odometer and the velocity measured by inertial sensors are taken as measurements. The semi-physical experiments are implemented to demonstrate that the position error can reduce to 10 m and attitude error is within 2″ during 5 min. The experiment results prove that it is an effective and attractive initialization approach for lunar rovers.

  8. A philosophy for CNS radiotracer design.

    Science.gov (United States)

    Van de Bittner, Genevieve C; Ricq, Emily L; Hooker, Jacob M

    2014-10-21

    Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available

  9. The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects

    OpenAIRE

    de Lange, Elizabeth CM

    2013-01-01

    Despite enormous advances in CNS research, CNS disorders remain the world?s leading cause of disability. This accounts for more hospitalizations and prolonged care than almost all other diseases combined, and indicates a high unmet need for good CNS drugs and drug therapies. Following dosing, not only the chemical properties of the drug and blood?brain barrier (BBB) transport, but also many other processes will ultimately determine brain target site kinetics and consequently the CNS effects. ...

  10. CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.

    Directory of Open Access Journals (Sweden)

    Christine M Matullo

    2011-12-01

    Full Text Available Although viruses have been implicated in central nervous system (CNS diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with both CNS-restricted measles virus (MV and peripherally restricted lymphocytic choriomeningitis virus (LCMV. While infection with either virus alone resulted in no illness, infection with both viruses caused disease in all mice, with ∼50% dying following seizures. Co-infection resulted in a 12-fold increase in the number of CD8+ T cells in the brain as compared to MV infection alone. Tetramer analysis revealed that a substantial proportion (>35% of these infiltrating CD8+ lymphocytes were LCMV-specific, despite no detectable LCMV in CNS tissues. Mechanistically, CNS disease was due to edema, induced in a CD8-dependent but perforin-independent manner, and brain herniation, similar to that observed in mice challenged intracerebrally with LCMV. These results indicate that T cell trafficking can be influenced by other ongoing immune challenges, and that CD8+ T cell recruitment to the brain can trigger CNS disease in the apparent absence of cognate antigen. By extrapolation, human CNS diseases of unknown etiology need not be associated with infection with any particular agent; rather, a condition that compromises and activates the blood-brain barrier and adjacent brain parenchyma can render the CNS susceptible to pathogen-independent immune attack.

  11. Basic Concepts of CNS Development.

    Science.gov (United States)

    Nowakowski, R. S.

    1987-01-01

    The goals of this review are to: (1) provide a set of concepts to aid in the understanding of complex processes which occur during central nervous system (CNS) development; (2) illustrate how they contribute to our knowlege of adult brain anatomy; and (3) delineate how modifications of normal developmental processes may affect the structure and…

  12. Engineering progress of CNS concept in Hanaro

    International Nuclear Information System (INIS)

    Choi, C.O.; Park, K.N.; Park, S.H.

    1997-01-01

    The Korea Atomic Energy research Institute (KAERI) strives to provide utilizing facilities on and around the Hanaro reactor in order to activate advanced researches by neutron application. As one of the facilities to be installed, the conceptual design work of CNS was started in 1996 with a project schedule of 5 years so that its installation work can be finished by the year 2000. And the major engineering targets of this CNS facility are established for a minimum physical interference with the present facilities of the Hanaro, a reach-out of very-high-gain factors in the cold neutron flux, a simplicity of the maintenance of the facility, and a safety in the operation of the facility as well as the reactor. For the conceptual design of Hanaro CNS, the experience of utilization and production of cold neutron at WWR-M reactor Gatchina, Russia has been used with that of elaborations for PIK reactor in design for neutron guide systems and instruments. (author)

  13. Application of empowerment theory for CNS practice.

    Science.gov (United States)

    Carlson-Catalano, J M

    1993-11-01

    Power is necessary for the clinical nurse specialist (CNS) to successfully conduct objectives of practice in bureaucratic hospital settings. To obtain power, the CNS could use strategies of an empowerment theory to fully operationalize roles in hospitals. This article will discuss how the CNS may be empowered utilizing strategies in four empowering categories. In addition, the many benefits of empowering the CNS are reviewed.

  14. Phantom limb pain: a case of maladaptive CNS plasticity?

    DEFF Research Database (Denmark)

    Flor, Herta; Nikolajsen, Lone; Jensen, Troels Staehelin

    2006-01-01

    might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human...

  15. Can injured adult CNS axons regenerate by recapitulating development?

    Science.gov (United States)

    Hilton, Brett J; Bradke, Frank

    2017-10-01

    In the adult mammalian central nervous system (CNS), neurons typically fail to regenerate their axons after injury. During development, by contrast, neurons extend axons effectively. A variety of intracellular mechanisms mediate this difference, including changes in gene expression, the ability to form a growth cone, differences in mitochondrial function/axonal transport and the efficacy of synaptic transmission. In turn, these intracellular processes are linked to extracellular differences between the developing and adult CNS. During development, the extracellular environment directs axon growth and circuit formation. In adulthood, by contrast, extracellular factors, such as myelin and the extracellular matrix, restrict axon growth. Here, we discuss whether the reactivation of developmental processes can elicit axon regeneration in the injured CNS. © 2017. Published by The Company of Biologists Ltd.

  16. Blue moon neurovirology: the merits of studying rare CNS diseases of viral origin.

    Science.gov (United States)

    O'Donnell, Lauren A; Rall, Glenn F

    2010-09-01

    While measles virus (MV) continues to have a significant impact on human health, causing 150,000-200,000 deaths worldwide each year, the number of fatalities that can be attributed to MV-triggered central nervous system (CNS) diseases are on the order of a few hundred individuals annually (World Health Organization 2009). Despite this modest impact, substantial effort has been expended to understand the basis of measles-triggered neuropathogenesis. What can be gained by studying such a rare condition? Simply stated, the wealth of studies in this field have revealed core principles that are relevant to multiple neurotropic pathogens, and that inform the broader field of viral pathogenesis. In recent years, the emergence of powerful in vitro systems, novel animal models, and reverse genetics has enabled insights into the basis of MV persistence, the complexity of MV interactions with neurons and the immune system, and the role of immune and CNS development in virus-triggered disease. In this review, we highlight some key advances, link relevant measles-based studies to the broader disciplines of neurovirology and viral pathogenesis, and propose future areas of study for the field of measles-mediated neurological disease.

  17. Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

    Science.gov (United States)

    Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

    2016-01-01

    The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

  18. Actuarial risk of isolated CNS involvement in Ewing's sarcoma following prophylactic cranial irradiation and intrathecal methotrexate

    International Nuclear Information System (INIS)

    Trigg, M.E.; Makuch, R.; Glaubiger, D.

    1985-01-01

    Records of 154 patients with Ewing's sarcoma treated at the National Cancer Institute were reviewed to assess the incidence and risk of developing isolated central nervous system (CNS) Ewing's sarcoma. Sixty-two of the 154 patients had received CNS irradiation and intrathecal (i.t.) methotrexate as part of their initial therapy to prevent the occurrence of isolated CNS Ewing's sarcoma. The risk of developing isolate CNS Ewing's sarcoma was greatest within the first two years after diagnosis and was approximately 10%. The overall risk of CNS recurrence in the group of patients receiving DNS treatment was similar to the group receiving no therapy directed to the CNS. The occurrence of isolated CNS involvement was not prevented by the use of CNS irradiation and i.t. methotrexate. Because of a lack of efficacy to the CNS irradiation regimen, current treatment regimens do not include therapy directed to CNS

  19. Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARγ/RORγt Pathway.

    Science.gov (United States)

    Zhang, Kai; Guo, Yawei; Ge, Zhenzhen; Zhang, Zhihui; Da, Yurong; Li, Wen; Zhang, Zimu; Xue, Zhenyi; Li, Yan; Ren, Yinghui; Jia, Long; Chan, Koon-Ho; Yang, Fengrui; Yan, Jun; Yao, Zhi; Xu, Aimin; Zhang, Rongxin

    2017-09-01

    T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

  20. Current approaches to enhance CNS delivery of drugs across the brain barriers

    Directory of Open Access Journals (Sweden)

    Lu CT

    2014-05-01

    Full Text Available Cui-Tao Lu,1 Ying-Zheng Zhao,2,3 Ho Lun Wong,4 Jun Cai,5 Lei Peng,2 Xin-Qiao Tian1 1The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, People’s Republic of China; 2Hainan Medical College, Haikou City, Hainan Province, People’s Republic of China; 3College of Pharmaceutical Sciences, Wenzhou Medical University, Zhejiang Province, People’s Republic of China; 4School of Pharmacy, Temple University, Philadelphia, PA, USA; 5Departments of Pediatrics and Anatomical Sciences and Neurobiology, University of Louisville School of Medicine Louisville, KY, USA Abstract: Although many agents have therapeutic potentials for central nervous system (CNS diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood–brain barrier and the blood–cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed. Keywords: drug delivery system, blood–brain barrier (BBB, central nervous system, brain-targeted therapy, cerebrospinal fluid (CSF

  1. Sleep disorders in children after treatment for a CNS tumour.

    Science.gov (United States)

    Verberne, Lisa M; Maurice-Stam, Heleen; Grootenhuis, Martha A; Van Santen, Hanneke M; Schouten-Van Meeteren, Antoinette Y N

    2012-08-01

    The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with clinical characteristics and daily performance (fatigue and psychosocial functioning). In a cross-sectional study at the outpatient clinic of the Emma Children's Hospital AMC (February-June 2010), sleep, fatigue and psychosocial functioning were analysed in 31 CNS tumour patients (mean age: 11.8years; 20 boys) and compared with 78 patients treated for a non-CNS malignancy (mean age: 9.7years; 41 boys) and norm data. Questionnaires applied were the Sleep Disorder Scale for Children, the Epworth Sleepiness Scale, the Pediatric Quality of Life Inventory, and the Strengths and Difficulties Questionnaire. Sleeping habits and endocrine deficiencies were assessed with a self-developed questionnaire. Increased somnolence was found in CNS tumour patients compared with those with a non-CNS malignancy (8.8±2.8 versus 7.5±2.7; Psleep. No specific risk factors were identified for a sleep disorder in CNS tumour patients, but their excessive somnolence was correlated with lower fatigue related quality of life (QoL) (r=-0.78, Psleep quality and diminish fatigue. © 2011 European Sleep Research Society.

  2. The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

    Science.gov (United States)

    Hucke, Stephanie; Herold, Martin; Liebmann, Marie; Freise, Nicole; Lindner, Maren; Fleck, Ann-Katrin; Zenker, Stefanie; Thiebes, Stephanie; Fernandez-Orth, Juncal; Buck, Dorothea; Luessi, Felix; Meuth, Sven G; Zipp, Frauke; Hemmer, Bernhard; Engel, Daniel Robert; Roth, Johannes; Kuhlmann, Tanja; Wiendl, Heinz; Klotz, Luisa

    2016-09-01

    Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses. In mice, FXR activation ameliorated CNS autoimmunity in an IL-10-dependent fashion and even suppressed advanced clinical disease upon therapeutic administration. In analogy to rodents, pharmacological FXR activation in human monocytes from healthy controls and MS patients induced an anti-inflammatory phenotype with suppressive properties including control of effector T cell proliferation. We therefore, propose an important role of FXR in control of T cell-mediated autoimmunity by promoting anti-inflammatory macrophage responses.

  3. Endovascular transplantation of stem cells to the injured rat CNS

    Energy Technology Data Exchange (ETDEWEB)

    Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan [Karolinska University Hospital, Department of Clinical Neuroscience, Karolinska Institutet, Department of Neuroradiology, Stockholm (Sweden); Le Blanc, Katarina [Karolinska University Hospital, Department of Stem Cell Research, Karolinska Institutet, Department of Clinical Immunology, Stockholm (Sweden)

    2009-10-15

    Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p<0.01) and 5 days (p<0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases. (orig.)

  4. Endovascular transplantation of stem cells to the injured rat CNS

    International Nuclear Information System (INIS)

    Lundberg, Johan; Soederman, Mikael; Andersson, Tommy; Holmin, Staffan; Le Blanc, Katarina

    2009-01-01

    Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p<0.01) and 5 days (p<0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases. (orig.)

  5. Prospective evaluation of delayed central nervous system (CNS) toxicity of hyperfractionated total body irradiation (TBI)

    International Nuclear Information System (INIS)

    Wenz, Frederik; Steinvorth, Sarah; Lohr, Frank; Fruehauf, Stefan; Wildermuth, Susanne; Kampen, Michael van; Wannenmacher, Michael

    2000-01-01

    Purpose: Prospective evaluation of chronic radiation effects on the healthy adult brain using neuropsychological testing of intelligence, attention, and memory. Methods and Materials: 58 patients (43 ± 10 yr) undergoing hyperfractionated total body irradiation (TBI) (TBI, 14.4 Gy, 12 x 1.2 Gy in 4 days) before bone marrow or peripheral blood stem cell transplantation were prospectively included. Twenty-one recurrence-free long-term survivors were re-examined 6-36 months (median 27 months) after completion of TBI. Neuropsychological testing included assessment of general intelligence, attention, and memory using normative, standardized psychometric tests. Mood status was controlled, as well. Test results are given as IQ scores (population mean 100) or percentiles for attention and memory (population mean 50). Results: The 21 patients showed normal baseline test results of IQ (101 ± 13) and attention (53 ± 28), with memory test scores below average (35 ± 21). Test results of IQ (98 ± 17), attention (58 ± 27), and memory (43 ± 28) showed no signs of clinically measurable radiation damage to higher CNS (central nervous system) functions during the follow-up. The mood status was improved. Conclusion: The investigation of CNS toxicity after hyperfractionated TBI showed no deterioration of test results in adult recurrence-free patients with tumor-free CNS. The median follow-up of 27 months will be extended.

  6. Cerebral blood flow variations in CNS lupus

    International Nuclear Information System (INIS)

    Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M.

    1990-01-01

    We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery

  7. Hendra and Nipah virus infection in cultured human olfactory epithelial cells

    NARCIS (Netherlands)

    Borisevich, V. (Viktoriya); Ozdener, M.H. (Mehmet Hakan); Malik, B. (Bilal); B. Rockx (Barry)

    2017-01-01

    textabstractHenipaviruses are emerging zoonotic viruses and causative agents of encephalitis in humans. However, the mechanisms of entry into the central nervous system (CNS) in humans are not known. Here, we evaluated the possible role of olfactory epithelium in virus entry into the CNS. We

  8. Distribution of transplanted human mesenchymal stem cells from Wharton’s Jelly in the central nervous systems of the EAE rats

    Directory of Open Access Journals (Sweden)

    Kovalchuk M. V.

    2015-10-01

    Full Text Available Human Wharton’s Jelly MSCs (hWJ-MSCs have a considerable advantage and potential in treating the central nervous system diseases and can be a new alternative treatment of Multiple Sclerosis (MS. Aim. To study the persistence and distribution of hWJ-MSCs along the neuraxis following transplantation in central nervous system of rats with experimental autoimmune encephalomyelitis (EAE, the animal model of MS. Methods. Isolation and cultivation of hWJ-MSCs in vitro. Immunological phenotyping by flow cytometry. EAE induction. Intrathecal (suboccipital injection of MSCs into CNS of SCH-induced EAE rats. Persistence of hWJ-MSCs in the CNS of hWJ-MSCs -treated rats was detected through detection of the human alpha-satellite DNA in the tissue sections and the cerebrospinal fluid (CSF by PCR at days 2, 3, 4 and 5 Results. PCR-assays for alpha-satellite sequences revealed that Human DNA was detected during 5 days following intrathecal injection at the peak of disease in the treated rats. It has been demonstrated that the human DNA was traced in CSF and various segments of a spinal cord. Conclusions. The data obtained suggest that intrathecally delivered hWJ-MSCs, with time, can migrate through the CSF from the injection site to various segments of CNS and persist therein during the first week of post transplantation, which was performed at the EAE disease peak in the xenogeneic setting without immunosuppression. hWJ-MSCs may be considered as a delivery cell source of therapeutic molecules for CNS inflammatory diseases.

  9. Therapy of CNS leukemia with intraventricular chemotherapy and low-dose neuraxis radiotherapy

    International Nuclear Information System (INIS)

    Steinherz, P.; Jereb, B.; Galicich, J.

    1985-01-01

    Successful treatment of CNS leukemic relapse has been frustrated by frequent local recurrence and eventual marrow relapse. The authors describe the treatment of meningeal leukemia in 39 children with intrathecal remission induction followed by the placement of an Ommaya reservoir to facilitate the administration and distribution of chemotherapeutic agents into the CSF. Six hundred or 900 rad of craniospinal radiation and maintenance intraventricular and intrathecal chemotherapy was then administered. Systemic reinduction therapy was added in the later cases. Sixteen children (41%) experienced no further events, with 17+ months to 13+ years (median, 25 months) follow-up . Eleven patients (28%) had CNS recurrence, nine (23%) bone marrow (BM) relapse, and two (5%) testicular relapse as the next adverse event. The course of patients with first isolated CNS relapse differed from that of the others. Eleven (69%) of 16 patients treated for first isolated CNS relapse are alive and 9 are event free, while only 35% of patients whose CNS relapse occurred simultaneously or after recurrent disease at other sites are alive (P = .04). Seven of 23 in the later group are event free. The difference is due to the increased incidence of BM relapse in the later group (30% v 6%; P = .04). For patients with first isolated CNS relapse, the life-table median CNS remission duration is 42 months. The projected CNS relapse-free survival and event-free survival 8 to 10 years after CNS relapse are 40% and 32%, respectively. Headache, nausea, and emesis of short duration were frequent during therapy. In three patients, the reservoir had to be removed for infection. No patient suffered neurologic deficit related to the reservoir. The therapy described can reduce the CNS relapse rate with manageable toxicity

  10. Study of Functional Status of CNS in Human-Operator in Conditions of Imitation Deep Spase Exploration

    Science.gov (United States)

    Marina, Skedina; Michael, Potapov; Anna, Kovaleva

    Functional status (FS) of CNS may influence human’s behavior and his professional activity. The purpose of study - analysis of FS CNS of human-operator in conditions of long-term isolation. The studies were conducted within the framework of the project «Mars-500» which simulates of interplanetary flight isolation conditions of different durations. We examined nine people aged from 26 to 40 years. Synchronous registration of classical bioelectric activity of brain (EEG) and a cerebral power exchange (a level of constant brain potential (LCP)) was carried out for study of functional status of CNS using the hardware-software complex «Neuro-KM - Omega-Neyroanalizator» (Ltd. «Statokin», Russia). The synchronical registration was performed in seven unipolar leads on a «10-20» (Fp1, Fp2, T3, T4, O1, O2, Cz) combined with the placement of reference electrode on the earlobe and «biological zero» electrode - on the wrist. During 105-days isolation with 3 volunteers on day 52 the following was observed: simultaneous displacement of α-rhythm localization, increase of its frequency by 10% with a decrease in the index and disorganization of α-activity, emergence of asymmetry. Appearance of LCP asymmetry for more than 5 mV (in one case - with a strong dominance of the left hemisphere) was registered with the overall reduction of the amplitude, indicating a stress reaction in isolation. Before 520-days isolation (6 volunteers) 3 from them had signs of stress reaction in accordance to EEG with: displacement of α-rhythm localization, increase of its frequency by 1-2 Hz and increase level LCP. During isolation before «exit on a surface of Mars» individual fluctuations of EEG and LCP were observed depending on the specifics of the crew activities. Directly «exit on a surface of Mars» for 2 volunteers of «crew of Mars» the increase in power of α-rhythm was observed. Other members of crew showed decrease power of α-rhythm. At various stages of experiment in 35

  11. Interneuron progenitor transplantation to treat CNS dysfunction

    Directory of Open Access Journals (Sweden)

    Muhammad O Chohan

    2016-08-01

    Full Text Available Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field.

  12. Bortezomib-related neuropathy may mask CNS relapse in multiple myeloma: A call for diligence.

    Science.gov (United States)

    Abid, Muhammad Bilal; De Mel, Sanjay; Abid, Muhammad Abbas; Tan, Kong Bing; Chng, Wee Joo

    2016-07-02

    Neuropathy is a common adverse effect of bortezomib. Isolated central nervous system (CNS) relapse in MM remains exceedingly rare and carries a dismal prognosis. We present an unusual case of bortezomib related neuropathy masking a CNS relapse of MM. A 57-year-old female was diagnosed with standard-risk MM with clinical and cytogenetic features not typically associated with CNS involvement. She was treated with 4 cycles of bortezomib/cyclophosphamide/dexamethasone (VCD) and achieved a VGPR, after which she underwent an autologous stem cell transplant (ASCT) followed by bortezomib maintenance. Six months after ASCT she developed symptoms suggestive of peripheral neuropathy which was attributed to bortezomib. However the symptoms persisted despite discontinuation of bortezomib. Imaging and cerebrospinal fluid analysis subsequently confirmed a CNS relapse. CNS involvement in MM (CNS-MM) is uncommon and is considered an aggressive disease. Recently published literature has reported biomarkers with prognostic potential. However, isolated CNS relapse is even less common; an event which carries a very poor prognosis. Given the heterogeneous neurologic manifestations associated with MM, clinical suspicion may be masked by confounding factors such as bortezomib-based therapy. The disease may further remain incognito if the patient does not exhibit any of the high risk features and biomarkers associated with CNS involvement. In the era of proteasome inhibitor (PtdIns)/immunomodulator (IMID)-based therapy for MM which carries neurologic adverse effects, it is prudent to consider CNS relapse early. This case further highlights the need for more robust biomarkers to predict CNS relapse and use of newer novel agents which demonstrate potential for CNS penetration.

  13. HB-GAM (pleiotrophin) reverses inhibition of neural regeneration by the CNS extracellular matrix

    Science.gov (United States)

    Paveliev, Mikhail; Fenrich, Keith K.; Kislin, Mikhail; Kuja-Panula, Juha; Kulesskiy, Evgeny; Varjosalo, Markku; Kajander, Tommi; Mugantseva, Ekaterina; Ahonen-Bishopp, Anni; Khiroug, Leonard; Kulesskaya, Natalia; Rougon, Geneviève; Rauvala, Heikki

    2016-01-01

    Chondroitin sulfate (CS) glycosaminoglycans inhibit regeneration in the adult central nervous system (CNS). We report here that HB-GAM (heparin-binding growth-associated molecule; also known as pleiotrophin), a CS-binding protein expressed at high levels in the developing CNS, reverses the role of the CS chains in neurite growth of CNS neurons in vitro from inhibition to activation. The CS-bound HB-GAM promotes neurite growth through binding to the cell surface proteoglycan glypican-2; furthermore, HB-GAM abrogates the CS ligand binding to the inhibitory receptor PTPσ (protein tyrosine phosphatase sigma). Our in vivo studies using two-photon imaging of CNS injuries support the in vitro studies and show that HB-GAM increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the adult spinal cord. Our findings may enable the development of novel therapies for CNS injuries. PMID:27671118

  14. Analysis of perfusion weighted image of CNS lymphoma

    International Nuclear Information System (INIS)

    Lee, In Ho; Kim, Sung Tae; Kim, Hyung-Jin; Kim, Keon Ha; Jeon, Pyoung; Byun, Hong Sik

    2010-01-01

    Purpose: It is difficult to differentiate CNS lymphoma from other tumors such as malignant gliomas, metastases, or meningiomas with conventional MR imaging, because the imaging findings are overlapped between these tumors. The purpose of this study is to investigate the perfusion weighted MR imaging findings of CNS lymphomas and to compare the relative cerebral blood volume ratios between CNS lymphomas and other tumors such as high grade gliomas, metastases, or meningiomas. Materials and methods: We retrospectively reviewed MRI findings and clinical records in 13 patients with pathologically proven CNS lymphoma between January 2006 and November 2008. We evaluated the relative cerebral blood volume ratios of tumor, which were obtained by dividing the values obtained from the normal white matter on MRI. Results: Total 13 patients (M:F = 8:5; age range 46-67 years, mean age 52.3 years) were included. The CNS lymphomas showed relatively low values of maximum relative CBV ratio in most patients regardless of primary or secondary CNS lymphoma. Conclusion: Perfusion weighted image may be helpful in the diagnosis of CNS lymphoma in spite of primary or secondary or B cell or T cell.

  15. Metallothionein expression and roles in the CNS

    DEFF Research Database (Denmark)

    Penkowa, Milena

    2002-01-01

      Metallothioneins (MTs) are low-molecular-weight (6-7 kDa) nonenzymatic proteins (60-68 amino acid residues, 25-30% being cysteine) expressed ubiquitous in the animal kingdom. In the central nervous system (CNS), three MT isoforms are known, namely MT-I to MT-III. MT-I and MT-II (MT...

  16. The retina as a window to the brain-from eye research to CNS disorders.

    Science.gov (United States)

    London, Anat; Benhar, Inbal; Schwartz, Michal

    2013-01-01

    Philosophers defined the eye as a window to the soul long before scientists addressed this cliché to determine its scientific basis and clinical relevance. Anatomically and developmentally, the retina is known as an extension of the CNS; it consists of retinal ganglion cells, the axons of which form the optic nerve, whose fibres are, in effect, CNS axons. The eye has unique physical structures and a local array of surface molecules and cytokines, and is host to specialized immune responses similar to those in the brain and spinal cord. Several well-defined neurodegenerative conditions that affect the brain and spinal cord have manifestations in the eye, and ocular symptoms often precede conventional diagnosis of such CNS disorders. Furthermore, various eye-specific pathologies share characteristics of other CNS pathologies. In this Review, we summarize data that support examination of the eye as a noninvasive approach to the diagnosis of select CNS diseases, and the use of the eye as a valuable model to study the CNS. Translation of eye research to CNS disease, and deciphering the role of immune cells in these two systems, could improve our understanding and, potentially, the treatment of neurodegenerative disorders.

  17. Glypicans and FGFs in CNS Development and Function

    NARCIS (Netherlands)

    Galli, Antonella

    2003-01-01

    One of the most important events during central nervous system (CNS) development is the communication between cells. Cell-to-cell signaling implicates the interaction between a signaling molecules (or ligands) and their receptors. Ligand-receptor interaction is a tightly regulated process and is

  18. Novel agents in CNS myeloma treatment.

    Science.gov (United States)

    Gozzetti, Alessandro; Cerase, Alfonso

    2014-01-01

    Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM.Treatment is still unsatisfactory. Many treatments have been described in the literature: chemotherapy (CHT), intrathecal therapy (IT), and radiotherapy (RT), with survivals reported between one month and six months. Recent drugs such as the immunomodulatory drugs (IMiDs) and proteasome inhibitors (bortezomib) have changed the treatment of patients with MM, both younger and older, with a significant improvement in response and survival. The activity of new drugs in CNSMM has been reported but is still not well known. Bortezomib does not cross the blood brain barrier (BBB), and IMID’s seem to have only a minimal crossover. The role of novel agents in CNS MM management will be discussed as well as the potential role of other new immunomodulatory drugs (pomalidomide) and proteasome inhibitors that seem to cross the BBB and hold promise into the treatment of this rare and still incurable localization of the disease.

  19. Intraoperative squash smear cytology in CNS lesions: A study of 150 pediatric cases

    Directory of Open Access Journals (Sweden)

    Arpita Jindal

    2017-01-01

    Full Text Available Background: Tumors of the central nervous system in the pediatric age group occur relatively frequently during the early years of life. Brain tumors are the most common solid malignancies of childhood and only second to acute childhood leukemia. Squash cytology is an indispensable diagnostic aid to central nervous system (CNS lesions. The definitive diagnosis of brain lesions is confirmed by histological examination. Aim: To study the cytology of CNS lesions in pediatric population and correlate it with histopathology. Materials and Methods: One hundred and fifty cases of CNS lesions in pediatric patients were studied over a period of 2 years. Intraoperative squash smears were prepared, stained with hematoxylin and eosin, and examined. Remaining sample was subjected to histopathological examination. Results: Medulloblastoma (24.0% was the most frequently encountered tumor followed by pilocyctic astrocytoma (21.33% and ependymoma (13.33%. Diagnostic accuracy of squash smear technique was 94.67% when compared with histological diagnosis. Conclusion: Smear cytology is a fairly accurate tool for intraoperative CNS consultations.

  20. Observations at the CNS-PNS border of ventral roots connected to a neuroma

    Directory of Open Access Journals (Sweden)

    Sten Remahl

    2010-10-01

    Full Text Available Previous studies have shown that numerous sprouts originating from a neuroma, after nerve injury in neonatal animals, can invade spinal nerve roots. In this study the border between the central and peripheral nervous system (CNS-PNS border of ventral roots in kittens was examined with both light and electron microscopy after early postnatal sciatic nerve resection. A transient ingrowth of substance P positive axons was observed into the CNS, but no spouts remained 6 weeks after the injury. Using serial sections and electron microscopy it was possible to identify small bundles of unmyelinated axons that penetrated from the root fascicles for a short distance into the CNS. These axons ended blindly, sometimes with a growth cone-like terminal swelling filled with vesicles. The axon bundles were accompanied by p75 positive cells in both the root fascicles and the pia mater, but not in the CNS. It may thus be suggested that neurotrophin presenting p75 positive cells could facilitate axonal growth into the pia mater and that the lack of such cells in the CNS compartment might contribute to the failure of growth into the CNS. A maldevelopment of myelin sheaths at the CNS-PNS border of motor axons was observed and it seems possible that this could have consequences for the propagation of action potential across this region after neonatal nerve injury.

  1. Protein phosphorylation systems in postmortem human brain

    International Nuclear Information System (INIS)

    Walaas, S.I.; Perdahl-Wallace, E.; Winblad, B.; Greengard, P.

    1989-01-01

    Protein phosphorylation systems regulated by cyclic adenosine 3',5'-monophosphate (cyclic AMP), or calcium in conjunction with calmodulin or phospholipid/diacylglycerol, have been studied by phosphorylation in vitro of particulate and soluble fractions from human postmortem brain samples. One-dimensional or two-dimensional gel electrophoretic protein separations were used for analysis. Protein phosphorylation catalyzed by cyclic AMP-dependent protein kinase was found to be highly active in both particulate and soluble preparations throughout the human CNS, with groups of both widely distributed and region-specific substrates being observed in different brain nuclei. Dopamine-innervated parts of the basal ganglia and cerebral cortex contained the phosphoproteins previously observed in rodent basal ganglia. In contrast, calcium/phospholipid-dependent and calcium/calmodulin-dependent protein phosphorylation systems were less prominent in human postmortem brain than in rodent brain, and only a few widely distributed substrates for these protein kinases were found. Protein staining indicated that postmortem proteolysis, particularly of high-molecular-mass proteins, was prominent in deeply located, subcortical regions in the human brain. Our results indicate that it is feasible to use human postmortem brain samples, when obtained under carefully controlled conditions, for qualitative studies on brain protein phosphorylation. Such studies should be of value in studies on human neurological and/or psychiatric disorders

  2. CNS Involvement in Hemophagocytic Lymphohistiocytosis: CT and MR Findings

    International Nuclear Information System (INIS)

    Chung, Tae Woong

    2007-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by proliferation of benign histiocytes, and this commonly involves the liver, spleen, lymph nodes, bone marrow and central nervous system (CNS). We report here on the CT and MR imaging findings in a case of CNS HLH that showed multiple ring enhancing masses mimicking abscess or another mass on the CT and MR imaging. emophagocytic lymphohistiocytosis (HLH) is a rare disorder that is characterized by nonmalignant diffuse infiltration of multiple organs, including the central nervous system (CNS), by lymphocytes and histiocytes (1). Many radiologic reports describing diffuse white matter infiltrations, parenchymal atrophy and calcification have been published, but the characteristics of these findings remain non-specific, especially in immunocompromised patients. We present here a case of HLH in a 3-year-old boy who presented with multiple ring enhancing lesions involving the brain. In conclusion, although the CT and MRI findings of HLH with ring enhancing parenchymal lesions are nonspecific and mimic abscess, and especially in the immunosuppressed patients, increased diffusion at the center on DWI may be a finding of HLH to differentiate it from abscess, which has restricted diffusion at the center. However, the pathologic correlation with DWI according to the lesion stage certainly needs further study with a larger number of patients

  3. CNS effects following the treatment of malignancy

    International Nuclear Information System (INIS)

    Rane, N.; Quaghebeur, G.

    2012-01-01

    Corporeal and central nervous system (CNS) axis chemotherapy and radiotherapy have long been used for the effective treatment and prophylaxis of CNS, body malignancies, and leukaemias. However, they are not without their problems. Following the proliferation of magnetic resonance neuroimaging in recent years it has become clear that the spectrum of toxicity that these therapies produce ranges from subclinical white matter changes to overt brain necrosis. The effects are both direct and indirect and via different pathological mechanisms. Chronic and progressive changes can be detected many years after the initial intervention. In addition to leucoencephalopathic changes, grey matter changes are now well described. Changes may be difficult to distinguish from tumour recurrence, though may be reversible and remediable, and are thus very important to differentiate. In this review toxic effects are classified and their imaging appearances discussed, with reference to specific syndromes.

  4. Therapeutic potential of agmatine for CNS disorders.

    Science.gov (United States)

    Neis, Vivian B; Rosa, Priscila B; Olescowicz, Gislaine; Rodrigues, Ana Lúcia S

    2017-09-01

    Agmatine is a neuromodulator that regulates multiple neurotransmitters and signaling pathways. Several studies have focused on elucidating the mechanisms underlying the neuroprotective effects of this molecule, which seems to be mediated by a reduction in oxidative damage, neuroinflammation, and proapoptotic signaling. Since these events are implicated in acute and chronic excitotoxicity-related disorders (ischemia, epilepsy, traumatic brain injury, spinal cord injury, neurodegenerative, and psychiatric disorders) as well as in nociception, agmatine has been proposed as a therapeutic strategy for the treatment of central nervous system (CNS) disorders. Agmatine also stimulates the expression of trophic factors and adult neurogenesis, contributing to its ability to induce endogenous repair mechanisms. Therefore, considering its wide range of biological effects, this review summarizes the current knowledge about its protective and regenerative properties in the CNS. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    DEFF Research Database (Denmark)

    Sturm, Dominik; Orr, Brent A; Toprak, Umut H

    2016-01-01

    with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration...

  6. CNS infections in immunocompetent patients

    International Nuclear Information System (INIS)

    Hartmann, K.M.; Zimmer, A.; Reith, W.

    2008-01-01

    This article gives a review of the most frequent infective agents reasonable for CNS infections in immunocompetent patients as well as their localisation and imaging specifications. MRI scanning is the gold standard to detect inflammatory conditions in the CNS. Imaging can be normal or nonspecifically altered although the infection is culturally or bioptically proven. There are no pathognomonic, pathogen-specific imaging criteria. The localization and dimension of the inflammation depends on the infection pathway. (orig.) [de

  7. The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury

    Science.gov (United States)

    Forbes, Lindsey H.

    2018-01-01

    The extracellular environment of the central nervous system (CNS) becomes highly structured and organized as the nervous system matures. The extracellular space of the CNS along with its subdomains plays a crucial role in the function and stability of the CNS. In this review, we have focused on two components of the neuronal extracellular environment, which are important in regulating CNS plasticity including the extracellular matrix (ECM) and myelin. The ECM consists of chondroitin sulfate proteoglycans (CSPGs) and tenascins, which are organized into unique structures called perineuronal nets (PNNs). PNNs associate with the neuronal cell body and proximal dendrites of predominantly parvalbumin-positive interneurons, forming a robust lattice-like structure. These developmentally regulated structures are maintained in the adult CNS and enhance synaptic stability. After injury, however, CSPGs and tenascins contribute to the structure of the inhibitory glial scar, which actively prevents axonal regeneration. Myelin sheaths and mature adult oligodendrocytes, despite their important role in signal conduction in mature CNS axons, contribute to the inhibitory environment existing after injury. As such, unlike the peripheral nervous system, the CNS is unable to revert to a “developmental state” to aid neuronal repair. Modulation of these external factors, however, has been shown to promote growth, regeneration, and functional plasticity after injury. This review will highlight some of the factors that contribute to or prevent plasticity, sprouting, and axonal regeneration after spinal cord injury. PMID:29849554

  8. Bovine-associated CNS species resist phagocytosis differently

    Science.gov (United States)

    2013-01-01

    Background Coagulase-negative staphylococci (CNS) cause usually subclinical or mild clinical bovine mastitis, which often remains persistent. Symptoms are usually mild, mostly only comprising slight changes in the appearance of milk and possibly slight swelling. However, clinical mastitis with severe signs has also been reported. The reasons for the differences in clinical expression are largely unknown. Macrophages play an important role in the innate immunity of the udder. This study examined phagocytosis and killing by mouse macrophage cells of three CNS species: Staphylococcus chromogenes (15 isolates), Staphylococcus agnetis (6 isolates) and Staphylococcus simulans (15 isolates). Staphylococcus aureus (7 isolates) was also included as a control. Results All the studied CNS species were phagocytosed by macrophages, but S. simulans resisted phagocytosis more effectively than the other CNS species. Only S. chromogenes was substantially killed by macrophages. Significant variations between isolates were seen in both phagocytosis and killing by macrophages and were more common in the killing assays. Significant differences between single CNS species and S. aureus were observed in both assays. Conclusion This study demonstrated that differences in the phagocytosis and killing of mastitis-causing staphylococci by macrophages exist at both the species and isolate level. PMID:24207012

  9. Gene therapy for CNS diseases – Krabbe disease

    Directory of Open Access Journals (Sweden)

    Mohammad A. Rafi

    2016-06-01

    Full Text Available This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases.

  10. EMMPRIN, an upstream regulator of MMPs, in CNS biology.

    Science.gov (United States)

    Kaushik, Deepak Kumar; Hahn, Jennifer Nancy; Yong, V Wee

    2015-01-01

    Matrix metalloproteinases (MMPs) are engaged in pathologies associated with infections, tumors, autoimmune disorders and neurological dysfunctions. With the identification of an upstream regulator of MMPs, EMMPRIN (Extracellular matrix metalloproteinase inducer, CD147), it is relevant to address if EMMPRIN plays a role in the pathology of central nervous system (CNS) diseases. This would enable the possibility of a more upstream and effective therapeutic target. Indeed, conditions including gliomas, Alzheimer's disease (AD), multiple sclerosis (MS), and other insults such as hypoxia/ischemia show elevated levels of EMMPRIN which correlate with MMP production. In contrast, given EMMPRIN's role in CNS homeostasis with respect to regulation of monocarboxylate transporters (MCTs) and interactions with adhesion molecules including integrins, we need to consider that EMMPRIN may also serve important regulatory or protective functions. This review summarizes the current understanding of EMMPRIN's involvement in CNS homeostasis, its possible roles in escalating or reducing neural injury, and the mechanisms of EMMPRIN including and apart from MMP induction. Copyright © 2015 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  11. Clearance of an immunosuppressive virus from the CNS coincides with immune reanimation and diversification

    Directory of Open Access Journals (Sweden)

    McGavern Dorian B

    2007-06-01

    Full Text Available Abstract Once a virus infection establishes persistence in the central nervous system (CNS, it is especially difficult to eliminate from this specialized compartment. Therefore, it is of the utmost importance to fully understand scenarios during which a persisting virus is ultimately purged from the CNS by the adaptive immune system. Such a scenario can be found following infection of adult mice with an immunosuppressive variant of lymphocytic choriomeningitis virus (LCMV referred to as clone 13. In this study we demonstrate that following intravenous inoculation, clone 13 rapidly infected peripheral tissues within one week, but more slowly inundated the entire brain parenchyma over the course of a month. During the establishment of persistence, we observed that genetically tagged LCMV-specific cytotoxic T lymphocytes (CTL progressively lost function; however, the severity of this loss in the CNS was never as substantial as that observed in the periphery. One of the most impressive features of this model system is that the peripheral T cell response eventually regains functionality at ~60–80 days post-infection, and this was associated with a rapid decline in virus from the periphery. Coincident with this "reanimation phase" was a massive influx of CD4 T and B cells into the CNS and a dramatic reduction in viral distribution. In fact, olfactory bulb neurons served as the last refuge for the persisting virus, which was ultimately purged from the CNS within 200 days post-infection. These data indicate that a functionally revived immune response can prevail over a virus that establishes widespread presence both in the periphery and brain parenchyma, and that therapeutic enhancement of an existing response could serve as an effective means to thwart long term CNS persistence.

  12. Morphological evaluation of fetus CNS and its related anomalies

    International Nuclear Information System (INIS)

    Oi, Shizuo; Tamaki, Norihiko; Matsumoto, Satoshi; Katayama, Kazuaki; Mochizuki, Matsuto

    1989-01-01

    The fetus central nervous system was evaluated morphologically by ultrasonography (US), magnetic resonance imaging (MRI), and CT scan to analyze the prenatal diagnostic value for CNS anomalies. A total of 31 patients with 42 lesions had been diagnosed during the preceding 7 years. The patients included 24 with hydrocephalus, three with anencephaly, three with myeloschisis, three with holoprosencephaly, three with an encephalocele, two with a Dandy-Walker cyst, one with hydroencephalodysplasia, one with an intracranial neoplasm, one with sacrococcygeal teratoma, and one with sacral agenesis. Compared with US and MRI, CT proved to be more accurate in the detection of spine and cranium-bone morphology. This finding seems to be valuable in the diagnosis of spina bifida, cranium bifidum and some cases of hypertensive hydrocephalus, especially in the axial view. MRI was definitely superior in the anatomico-pathological diagnosis of cerebral dysgenesis, ventriculomegaly, intracranial tumors, and other brain parenchymal changes in view of multi-dimensional analysis. The most considerable disadvantage of MRI in the diagnosis of a fetus CNS anomaly is the poor information about spine and cranium morphology. A super-conducting MRI system is still insufficient to demonstrate the spinal cord of a fetus. US was routinely used, and the multidimensional slices were useful for screening the CNS abnormalies. Some of the fetus brain lesions, such as intracranial hematomas, had a specific echogenecity on US. However, US sometimes failed to demarcate the cerebral parenchymal or subdural morphological changes because its artifacts had hyperchoic shadows. While US, MRI, and CT were valuable diagnostic tools in the morphological evaluation of fetus CNS and its related anomalies, each modality has different diagnostic advantages and disadvantages. Improvement can be expected when these diagnostic imaging modalities are complementary, depending upon the nature of the anatomy. (J.P.N.)

  13. Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice.

    Directory of Open Access Journals (Sweden)

    Jean Rodgers

    Full Text Available Invasion of the central nervous system (CNS by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.

  14. Mining the topography and dynamics of the 4D Nucleome to identify novel CNS drug pathways.

    Science.gov (United States)

    Higgins, Gerald A; Allyn-Feuer, Ari; Georgoff, Patrick; Nikolian, Vahagn; Alam, Hasan B; Athey, Brian D

    2017-07-01

    The pharmacoepigenome can be defined as the active, noncoding province of the genome including canonical spatial and temporal regulatory mechanisms of gene regulation that respond to xenobiotic stimuli. Many psychotropic drugs that have been in clinical use for decades have ill-defined mechanisms of action that are beginning to be resolved as we understand the transcriptional hierarchy and dynamics of the nucleus. In this review, we describe spatial, temporal and biomechanical mechanisms mediated by psychotropic medications. Focus is placed on a bioinformatics pipeline that can be used both for detection of pharmacoepigenomic variants that discretize drug response and adverse events to improve pharmacogenomic testing, and for the discovery of novel CNS therapeutics. This approach integrates the functional topology and dynamics of the transcriptional hierarchy of the pharmacoepigenome, gene variant-driven identification of pharmacogenomic regulatory domains, and mesoscale mapping for the discovery of novel CNS pharmacodynamic pathways in human brain. Examples of the application of this pipeline are provided, including the discovery of valproic acid (VPA) mediated transcriptional reprogramming of neuronal cell fate following injury, and mapping of a CNS pathway glutamatergic pathway for the mood stabilizer lithium. These examples in regulatory pharmacoepigenomics illustrate how ongoing research using the 4D nucleome provides a foundation to further insight into previously unrecognized psychotropic drug pharmacodynamic pathways in the human CNS. Copyright © 2017. Published by Elsevier Inc.

  15. Immunohistological localization of serotonin in the CNS and feeding system of the stable fly stomoxys calcitrans L. (Diptera: muscidae)

    Science.gov (United States)

    Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR)to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stab...

  16. Maternal stress, nutrition and physical activity: Impact on immune function, CNS development and psychopathology.

    Science.gov (United States)

    Marques, Andrea Horvath; Bjørke-Monsen, Anne-Lise; Teixeira, Antônio L; Silverman, Marni N

    2015-08-18

    Evidence suggests that maternal and fetal immune dysfunction may impact fetal brain development and could play a role in neurodevelopmental disorders, although the definitive pathophysiological mechanisms are still not completely understood. Stress, malnutrition and physical inactivity are three maternal behavioral lifestyle factors that can influence immune and central nervous system (CNS) functions in both the mother and fetus, and may therefore, increase risk for neurodevelopmental/psychiatric disorders. First, we will briefly review some aspects of maternal-fetal immune system interactions and development of immune tolerance. Second, we will discuss the bidirectional communication between the immune system and CNS and the pathways by which immune dysfunction could contribute to neurodevelopmental disorders. Third, we will discuss the effects of prenatal stress and malnutrition (over and undernutrition) on perinatal programming of the CNS and immune system, and how this might influence neurodevelopment. Finally, we will discuss the beneficial impact of physical fitness during pregnancy on the maternal-fetal unit and infant and how regular physical activity and exercise can be an effective buffer against stress- and inflammatory-related disorders. Although regular physical activity has been shown to promote neuroplasticity and an anti-inflammatory state in the adult, there is a paucity of studies evaluating its impact on CNS and immune function during pregnancy. Implementing stress reduction, proper nutrition and ample physical activity during pregnancy and the childbearing period may be an efficient strategy to counteract the impact of maternal stress and malnutrition/obesity on the developing fetus. Such behavioral interventions could have an impact on early development of the CNS and immune system and contribute to the prevention of neurodevelopmental and psychiatric disorders. Further research is needed to elucidate this relationship and the underlying

  17. Redox Signaling Mediated by Thioredoxin and Glutathione Systems in the Central Nervous System.

    Science.gov (United States)

    Ren, Xiaoyuan; Zou, Lili; Zhang, Xu; Branco, Vasco; Wang, Jun; Carvalho, Cristina; Holmgren, Arne; Lu, Jun

    2017-11-01

    The thioredoxin (Trx) and glutathione (GSH) systems play important roles in maintaining the redox balance in the brain, a tissue that is prone to oxidative stress due to its high-energy demand. These two disulfide reductase systems are active in various areas of the brain and are considered to be critical antioxidant systems in the central nervous system (CNS). Various neuronal disorders have been characterized to have imbalanced redox homeostasis. Recent Advances: In addition to their detrimental effects, recent studies have highlighted that reactive oxygen species/reactive nitrogen species (ROS/RNS) act as critical signaling molecules by modifying thiols in proteins. The Trx and GSH systems, which reversibly regulate thiol modifications, regulate redox signaling involved in various biological events in the CNS. In this review, we focus on the following: (i) how ROS/RNS are produced and mediate signaling in CNS; (ii) how Trx and GSH systems regulate redox signaling by catalyzing reversible thiol modifications; (iii) how dysfunction of the Trx and GSH systems causes alterations of cellular redox signaling in human neuronal diseases; and (iv) the effects of certain small molecules that target thiol-based signaling pathways in the CNS. Further study on the roles of thiol-dependent redox systems in the CNS will improve our understanding of the pathogenesis of many human neuronal disorders and also help to develop novel protective and therapeutic strategies against neuronal diseases. Antioxid. Redox Signal. 27, 989-1010.

  18. Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

    Science.gov (United States)

    Malik, Jai; Karan, Maninder; Vasisht, Karan

    2011-12-01

    Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.

  19. Intellectual abilities among survivors of childhood leukaemia as a function of CNS irradiation

    International Nuclear Information System (INIS)

    Eiser, C.

    1978-01-01

    Twenty-eight children in remission at least 2 years after completing chemotherapy for acute lymphoblastic leukaemia were assessed on standardised psychological tests. It was found that 7 who never had central nervous system (CNS) irradiation and 9 having prophylactic CNS irradiation at least 6 months after diagnosis tended to perform at average or above levels, while those 10 each having prophylactic CNS irradiation (within 2 months of diagnosis) were generally at lower ability. Within the latter group 3 children showed serious intellectual impairments, while the group as a whole functioned especially poorly on quantitative tasks and those involving speeded performance with abstract material. General language ability was not affected. Practical and theoretical implications are discussed. (author)

  20. Analysis of neurocognitive function and CNS endpoints in the PROTEA trial

    DEFF Research Database (Denmark)

    Clarke, Amanda; Johanssen, Veronika; Gerstoft, Jan

    2014-01-01

    INTRODUCTION: During treatment with protease inhibitor monotherapy, the number of antiretrovirals with therapeutic concentrations in the cerebrospinal fluid (CSF) is lower, compared to standard triple therapy. However, the clinical consequences are unclear. METHODS: A total of 273 patients with HIV...... and the Grooved Pegboard Test at screening, baseline and at Week 48. A global neurocognitive score (NPZ-5) was derived by averaging the standardized results of the five domains. In a central nervous system (CNS) sub-study (n=70), HIV RNA levels in the CNS were evaluated at baseline and Week 48. Clinical adverse...... events related to the CNS were collected at each visit. RESULTS: Patients were 83% male and 88% White, with median age 43 years. There were more patients with nadir CD4 count below 200 cells/µL in the DRV/r monotherapy arm (41/137, 30%) than the triple therapy arm (30/136, 22%). At Week 48...

  1. CNS adverse events associated with antimalarial agents. Fact or fiction?

    NARCIS (Netherlands)

    Phillips-Howard, P. A.; ter Kuile, F. O.

    1995-01-01

    CNS adverse drug events are dramatic, and case reports have influenced clinical opinion on the use of antimalarials. Malaria also causes CNS symptoms, thus establishing causality is difficult. CNS events are associated with the quinoline and artemisinin derivatives. Chloroquine, once considered too

  2. Regulation of Adult CNS Axonal Regeneration by the Post-transcriptional Regulator Cpeb1

    Directory of Open Access Journals (Sweden)

    Wilson Pak-Kin Lou

    2018-01-01

    Full Text Available Adult mammalian central nervous system (CNS neurons are unable to regenerate following axonal injury, leading to permanent functional impairments. Yet, the reasons underlying this regeneration failure are not fully understood. Here, we studied the transcriptome and translatome shortly after spinal cord injury. Profiling of the total and ribosome-bound RNA in injured and naïve spinal cords identified a substantial post-transcriptional regulation of gene expression. In particular, transcripts associated with nervous system development were down-regulated in the total RNA fraction while remaining stably loaded onto ribosomes. Interestingly, motif association analysis of post-transcriptionally regulated transcripts identified the cytoplasmic polyadenylation element (CPE as enriched in a subset of these transcripts that was more resistant to injury-induced reduction at the transcriptome level. Modulation of these transcripts by overexpression of the CPE binding protein, Cpeb1, in mouse and Drosophila CNS neurons promoted axonal regeneration following injury. Our study uncovered a global evolutionarily conserved post-transcriptional mechanism enhancing regeneration of injured CNS axons.

  3. 3rd ENRI International Workshop on ATM/CNS

    CERN Document Server

    2014-01-01

    The Electronic Navigation Research Institute (ENRI) held its third International Workshop on ATM / CNS in 2013 with the theme of "Drafting the future sky". There is worldwide activity taking place in the research and development of modern air traffic management (ATM) and its enabling technologies in Communication, Navigation and Surveillance (CNS). Pioneering work is necessary to contribute to the global harmonization of air traffic management and control. At this workshop, leading experts in  research, industry and academia from around the world met to share their ideas and approaches on ATM/CNS related topics.

  4. CNS penetration of ART in HIV-infected children

    NARCIS (Netherlands)

    van den Hof, Malon; Blokhuis, Charlotte; Cohen, Sophie; Scherpbier, Henriette J.; Wit, Ferdinand W. N. M.; Pistorius, M. C. M.; Kootstra, Neeltje A.; Teunissen, Charlotte E.; Mathot, Ron A. A.; Pajkrt, Dasja

    2018-01-01

    Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce. Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function. Patients and methods: Antiretroviral drug levels were measured in paired

  5. Distribution of CNS Species on Teat Skin and in Milk Samples from Dairy Cows in Automatic Milking Systems

    DEFF Research Database (Denmark)

    Mahmmod, Yasser; Svennesen, Line; Pedersen, Karl

    identified in milk samples. Staphylococcus chromogenes was detected in both milk (n= 2) and teat skin (n= 1) samples. Data collection will be finished in April 2017. The final results will give new insights into herd specific CNS species patterns and the microbial ecology and epidemiology of common CNS...

  6. CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System.

    Directory of Open Access Journals (Sweden)

    Rebecca A Drummond

    2015-12-01

    Full Text Available Candida is the most common human fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous fungal disease that targets the central nervous system (CNS. However, how CARD9 promotes protective antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS fungal susceptibility of CARD9-deficient humans.

  7. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    NARCIS (Netherlands)

    Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T. W.; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; von Bueren, André O.; von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; van Meter, Timothy; Monoranu, Camelia-Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

    2016-01-01

    Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally

  8. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs

    NARCIS (Netherlands)

    Sturm, Dominik; Orr, Brent A.; Toprak, Umut H.; Hovestadt, Volker; Jones, David T W; Capper, David; Sill, Martin; Buchhalter, Ivo; Northcott, Paul A.; Leis, Irina; Ryzhova, Marina; Koelsche, Christian; Pfaff, Elke; Allen, Sariah J.; Balasubramanian, Gnanaprakash; Worst, Barbara C.; Pajtler, Kristian W.; Brabetz, Sebastian; Johann, Pascal D.; Sahm, Felix; Reimand, Jüri; Mackay, Alan; Carvalho, Diana M.; Remke, Marc; Phillips, Joanna J.; Perry, Arie; Cowdrey, Cynthia; Drissi, Rachid; Fouladi, Maryam; Giangaspero, Felice; Łastowska, Maria; Grajkowska, Wiesława; Scheurlen, Wolfram; Pietsch, Torsten; Hagel, Christian; Gojo, Johannes; Lötsch, Daniela; Berger, Walter; Slavc, Irene; Haberler, Christine; Jouvet, Anne; Holm, Stefan; Hofer, Silvia; Prinz, Marco; Keohane, Catherine; Fried, Iris; Mawrin, Christian; Scheie, David; Mobley, Bret C.; Schniederjan, Matthew J.; Santi, Mariarita; Buccoliero, Anna M.; Dahiya, Sonika; Kramm, Christof M.; Von Bueren, André O.; Von Hoff, Katja; Rutkowski, Stefan; Herold-Mende, Christel; Frühwald, Michael C.; Milde, Till; Hasselblatt, Martin; Wesseling, Pieter; Rößler, Jochen; Schüller, Ulrich; Ebinger, Martin; Schittenhelm, Jens; Frank, Stephan; Grobholz, Rainer; Vajtai, Istvan; Hans, Volkmar; Schneppenheim, Reinhard; Zitterbart, Karel; Collins, V. Peter; Aronica, Eleonora; Varlet, Pascale; Puget, Stephanie; Dufour, Christelle; Grill, Jacques; Figarella-Branger, Dominique; Wolter, Marietta; Schuhmann, Martin U.; Shalaby, Tarek; Grotzer, Michael; Van Meter, Timothy; Monoranu, Camelia Maria; Felsberg, Jörg; Reifenberger, Guido; Snuderl, Matija; Forrester, Lynn Ann; Koster, Jan; Versteeg, Rogier; Volckmann, Richard; Van Sluis, Peter; Wolf, Stephan; Mikkelsen, Tom; Gajjar, Amar; Aldape, Kenneth; Moore, Andrew S.; Taylor, Michael D.; Jones, Chris; Jabado, Nada; Karajannis, Matthias A.; Eils, Roland; Schlesner, Matthias; Lichter, Peter; Von Deimling, Andreas; Pfister, Stefan M.; Ellison, David W.; Korshunov, Andrey; Kool, Marcel

    2016-01-01

    Summary Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of

  9. Thyroid Hormone in the CNS: Contribution of Neuron-Glia Interaction.

    Science.gov (United States)

    Noda, Mami

    2018-01-01

    The endocrine system and the central nervous system (CNS) are intimately linked. Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the regulation of development and differentiation of neurons and neuroglia and hence for development and function of the CNS. T3 (3,3',5-triiodothyronine), an active form of TH, is important not only for neuronal development but also for differentiation of astrocytes and oligodendrocytes, and for microglial development. In adult brain, T3 affects glial morphology with sex- and age-dependent manner and therefore may affect their function, leading to influence on neuron-glia interaction. T3 is an important signaling factor that affects microglial functions such as migration and phagocytosis via complex mechanisms. Therefore, dysfunction of THs may impair glial function as well as neuronal function and thus disturb the brain, which may cause mental disorders. Investigations on molecular and cellular basis of hyperthyroidism and hypothyroidism will help us to understand changes in neuron-glia interaction and therefore consequent psychiatric symptoms. © 2018 Elsevier Inc. All rights reserved.

  10. Prophylactic CNS therapy in childhood leukemia

    International Nuclear Information System (INIS)

    Yokoyama, Takashi; Hiyoshi, Yasuhiko; Fujimoto, Takeo

    1982-01-01

    This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm 3 ) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm 3 ) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m 2 ) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m 2 , the CSF concentration of MTX rose to 2.3 +- 2.4 x 10 -6 M after initiation of infusion and remained in 10 -7 M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% i n Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC. (author)

  11. Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination.

    Directory of Open Access Journals (Sweden)

    Jasmin Nessler

    Full Text Available For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE, an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS. In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.

  12. Sleep disorders in children after treatment for a CNS tumour

    NARCIS (Netherlands)

    Verberne, Lisa M.; Maurice-Stam, Heleen; Grootenhuis, Martha A.; van Santen, Hanneke M.; Schouten-van Meeteren, Antoinette Y. N.

    2012-01-01

    The long-term survival of children with a central nervous system (CNS) tumour is improving. However, they experience late effects, including altered habits and patterns of sleep. We evaluated the presence and type of sleep disorders and daytime sleepiness in these children, and its associations with

  13. Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.

    Science.gov (United States)

    Mayfield, Jody; Blednov, Yuri A; Harris, R Adron

    2015-01-01

    G protein-coupled inwardly rectifying potassium (GIRK) channels are widely expressed throughout the brain and mediate the inhibitory effects of many neurotransmitters. As a result, these channels are important for normal CNS function and have also been implicated in Down syndrome, Parkinson's disease, psychiatric disorders, epilepsy, and drug addiction. Knockout mouse models have provided extensive insight into the significance of GIRK channels under these conditions. This review examines the behavioral and genetic evidence from animal models and genetic association studies in humans linking GIRK channels with CNS disorders. We further explore the possibility that subunit-selective modulators and other advanced research tools will be instrumental in establishing the role of individual GIRK subunits in drug addiction and other relevant CNS diseases and in potentially advancing treatment options for these disorders. © 2015 Elsevier Inc. All rights reserved.

  14. Human iPSC for Therapeutic Approaches to the Nervous System: Present and Future Applications

    Directory of Open Access Journals (Sweden)

    Maria Giuseppina Cefalo

    2016-01-01

    Full Text Available Many central nervous system (CNS diseases including stroke, spinal cord injury (SCI, and brain tumors are a significant cause of worldwide morbidity/mortality and yet do not have satisfying treatments. Cell-based therapy to restore lost function or to carry new therapeutic genes is a promising new therapeutic approach, particularly after human iPSCs became available. However, efficient generation of footprint-free and xeno-free human iPSC is a prerequisite for their clinical use. In this paper, we will first summarize the current methodology to obtain footprint- and xeno-free human iPSC. We will then review the current iPSC applications in therapeutic approaches for CNS regeneration and their use as vectors to carry proapoptotic genes for brain tumors and review their applications for modelling of neurological diseases and formulating new therapeutic approaches. Available results will be summarized and compared. Finally, we will discuss current limitations precluding iPSC from being used on large scale for clinical applications and provide an overview of future areas of improvement. In conclusion, significant progress has occurred in deriving iPSC suitable for clinical use in the field of neurological diseases. Current efforts to overcome technical challenges, including reducing labour and cost, will hopefully expedite the integration of this technology in the clinical setting.

  15. Evaluation of cell proliferation, apoptosis, and dna-repair genes as potential biomarkers for ethanol-induced cns alterations

    Directory of Open Access Journals (Sweden)

    Hicks Steven D

    2012-10-01

    Full Text Available Abstract Background Alcohol use disorders (AUDs lead to alterations in central nervous system (CNS architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. Results Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1 was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5 showed a highly significant correlation with AUD-induced decreases in the volume of the left

  16. Elevated interferon-gamma in CNS inflammatory disease: a potential complication for bone marrow reconstitution in MS

    DEFF Research Database (Denmark)

    Hassan-Zahraee, M; Tran, E H; Bourbonnière, L

    2000-01-01

    but levels were higher in IFNgamma transgenics. BM transplantation into IFNgamma-deficient recipients also had a high failure rate. Transplants of BM from mice lacking expression of IFNgamma-receptor failed, whereas IFNgamma-deficient grafts survived, suggesting that IFNgamma response status of the graft can......Bone marrow transplantation (BMT) is increasingly used to treat Multiple Sclerosis (MS) a CNS inflammatory disease with elevated CNS and systemic IFNgamma levels. We wished to determine the effect of IFNgamma on BM graft survival in a transgenic mouse model for chronic MS. BM transplantation...... into transgenic mice which express elevated levels of IFNgamma in the CNS was unsuccessful. By contrast, there was 100% survival of even fully allogeneic, T-depleted transplants to transgenics that over express TNFalpha in the CNS, using the same MBP promoter. IFNgamma was detectable in spleen of irradiated mice...

  17. Autoimmune process in CNS under Cs-137 inner irradiation

    International Nuclear Information System (INIS)

    Lisyany, N.I.; Liubich, L.D.

    1996-01-01

    Autoimmune hypothesis as to the development of radiation-induced brain injuries stands high among the concepts of the CNS post-radiation damage pathogenesis. To study the changes occurring in a living organism affected by a small-dose radiation due to incorporated radionuclides as well as to create adequate models are of critical importance in the post-Chernobyl period. The effects of chronic small-dose inner radiation on the development of autoimmune responses were evaluated by determining the level of the CNS proteins and protein-induced antibodies to the CNS components. (author)

  18. AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.

    Science.gov (United States)

    Ivachtchenko, Alexandre V; Lavrovsky, Yan; Okun, Ilya

    2016-05-25

    Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

  19. Imaging of systemic lupus erythematosus. Part I: CNS, cardiovascular, and thoracic manifestations

    International Nuclear Information System (INIS)

    Goh, Y.P.; Naidoo, P.; Ngian, G.S.

    2013-01-01

    Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease that has a relapsing and remitting course. It has a wide range of non-specific symptoms with various organ manifestations. In 1982, the American College of Rheumatology (ACR) published the revised criteria for the classification of SLE. The diagnosis of SLE may be made if four or more of the 11 ACR criteria are present, either serially or simultaneously, during any interval of observation. Whilst the diagnosis of SLE is based on clinical and laboratory features, with no universally accepted radiological diagnostic criteria, imaging is nonetheless useful for diagnosing specific organ manifestations, monitoring disease progression, and identifying complications secondary to immunosuppressive therapy. In this review, we describe the spectrum of radiological findings of SLE in various organ systems and compile a list of organ manifestations including the most frequently occurring diseases as well as the rare but not-to-be-missed diseases. This review aims to serve as a concise reference tool in an endeavour to assist clinicians and radiologists in the diagnosis and monitoring of this disease. This pictorial review presents the various radiological findings of CNS, cardiovascular and thoracic manifestation of SLE. The gastrointestinal, renal and musculoskeletal systems will be covered in part II.

  20. Serial brain MRI findings in CNS involvement of familial erythrophagocytic lymphohistiocytosis: a case report

    International Nuclear Information System (INIS)

    Cho, Kyung Soo; Yoo, Jeong Hyun; Suh, Jeong Soo; Ryu, Kyung Ha; Hong, Ki Sook; Kim, Hak Jin

    2002-01-01

    Familial erythrophagocytic lymphohistiocytosis is a fatal early childhood disorder characterized by multiorgan lymphohistiocytic infiltration and active hemophagocytosis. Involvement of the central nervous system (CNS) is not uncommon and is characterized by rapidly progressive tissue damage affecting both the gray and white matter. We encountered a case of familial erythrophagocytic lymphohistiocytosis with CNS involvement. Initial T2-weighted MRI of the brain demonstrated high signal intensity in the right thalamus, though after chemotherapy, which led to the relief of neurologic symptoms, this disappeared. After four months. however, the patient's neurologic symptoms recurred, and follow-up T2-weighted MR images showed high signal intensity in the thalami, basal ganglia, and cerebral and cerebellar white matter. Brain MRI is a useful imaging modality for the evaluation of CNS involvement and monitoring the response to treatment

  1. Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure

    Science.gov (United States)

    Nelson, Gregory A.; Simonsen, Lisa; Huff, Janice L.

    2016-01-01

    Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are concerns for human exploration of space. Acute CNS risks may include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks may include neurological disorders such as Alzheimer's disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and 9 protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs.

  2. CNS-targets in control of energy and glucose homeostasis.

    Science.gov (United States)

    Kleinridders, André; Könner, A Christine; Brüning, Jens C

    2009-12-01

    The exceeding efforts in understanding the signals initiated by nutrients and hormones in the central nervous system (CNS) to regulate glucose and energy homeostasis have largely revolutionized our understanding of the neurocircuitry in control of peripheral metabolism. The ability of neurons to sense nutrients and hormones and to adopt a coordinated response to these signals is of crucial importance in controlling food intake, energy expenditure, glucose and lipid metabolism. Anatomical lesion experiments, pharmacological inhibition of signaling pathways, and, more recently, the analysis of conditional mouse mutants with modifications of hormone and nutrient signaling in defined neuronal populations have broadened our understanding of these complex neurocircuits. This review summarizes recent findings regarding the role of the CNS in sensing and transmitting nutritional and hormonal signals to control energy and glucose homeostasis and aims to define them as potential novel drug targets for the treatment of obesity and type 2 diabetes mellitus.

  3. Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.

    Science.gov (United States)

    Storm, J E; Rozman, K K

    1998-06-01

    The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.

  4. Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

    Science.gov (United States)

    de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

    2017-06-01

    Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

  5. P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.

    Science.gov (United States)

    Davis, Thomas P; Sanchez-Covarubias, Lucy; Tome, Margaret E

    2014-01-01

    The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. © 2014 Elsevier Inc. All rights reserved.

  6. 4th ENRI International Workshop on ATM/CNS

    CERN Document Server

    2017-01-01

    This book is a compilation of selected papers from the 4th ENRI International Workshop on ATM/CNS (EIWAC2015). The work focuses on novel techniques for aviation infrastructure in air traffic management (ATM) and communications, navigation, surveillance, and informatics (CNSI) domains. The contents make valuable contributions to academic researchers, engineers in the industry, and regulators of aviation authorities. As well, readers will encounter new ideas for realizing a more efficient and safer aviation system. .

  7. Chemokines in the balance: maintenance of homeostasis and protection at CNS barriers

    Directory of Open Access Journals (Sweden)

    Jessica L Williams

    2014-05-01

    Full Text Available In the adult central nervous system (CNS, chemokines and their receptors are involved in developmental, physiological and pathological processes. Although most lines of investigation focus on their ability to induce the migration of cells, recent studies indicate that chemokines also promote cellular interactions and activate signaling pathways that maintain CNS homeostatic functions. Many homeostatic chemokines are expressed on the vasculature of the blood brain barrier including CXCL12, CCL19, CCL20, and CCL21. While endothelial cell expression of these chemokines is known to regulate the entry of leukocytes into the CNS during immunosurveillance, new data indicate that CXCL12 is also involved in diverse cellular activities including adult neurogenesis and neuronal survival, having an opposing role to the homeostatic chemokine, CXCL14, which appears to regulate synaptic inputs to neural precursors. Neuronal expression of CX3CL1, yet another homeostatic chemokine that promotes neuronal survival and communication with microglia, is partly regulated by CXCL12. Regulation of CXCL12 is unique in that it may regulate its own expression levels via binding to its scavenger receptor CXCR7/ACKR3. In this review, we explore the diverse roles of these and other homeostatic chemokines expressed within the CNS, including the possible implications of their dysfunction as a cause of neurologic disease.

  8. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    Science.gov (United States)

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  9. Inflammatory cytokines in the brain: does the CNS shape immune responses?

    Science.gov (United States)

    Owens, T; Renno, T; Taupin, V; Krakowski, M

    1994-12-01

    Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far from being an immunologically privileged organ, T lymphocytes may be regular and frequent visitors to the CNS, for purposes of immune surveillance. Here, Trevor Owens and colleagues propose that the brain itself can regulate or shape immune responses therein. Furthermore, given that the immune cells may be subverted to autoimmunity, they suggest that the study of inflammatory autoimmune disease in the brain may shed light on the ability of the local environment to regulate immune responses.

  10. Inflammatory cytokines in the brain: does the CNS shape immune responses?

    DEFF Research Database (Denmark)

    Owens, T; Renno, T; Taupin, V

    1994-01-01

    Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far ...

  11. Enhancing Psychosocial Outcomes for Young Adult Childhood CNS Cancer Survivors: Importance of Addressing Vocational Identity and Community Integration

    Science.gov (United States)

    Strauser, David R.; Wagner, Stacia; Wong, Alex W. K.

    2012-01-01

    The purpose of this study was to examine the relationship between vocational identity, community integration, positive and negative affect, and satisfaction with life in a group of young adult central nervous system (CNS) cancer survivors. Participants in this study included 45 young adult CNS cancer survivors who ranged in age from 18 to 30 years…

  12. BRAINSTEM AUDITORY EVOKED POTENTIAL AS AN INDEX OF CNS DEMYELINATION IN GUILLAIN -BARRÉ SYNDROME (GBS

    Directory of Open Access Journals (Sweden)

    Smita Singh

    2016-01-01

    Full Text Available Background: Guillain-Barré Syndrome (GBS is an acute, frequently severe and fulminant polyradicular neuropathy that is autoimmune in nature. GBS manifest as rapidly evolving areflexic motor paralysis with or without sensory disturbances. It mainly involves peripheral nervous system and autonomic nervous system. There are rare evidences about the involvement of central nervous system (CNS in GBS. Aims: The main objective of the study was to assess the CNS involvement in GBS using the Brainstem Auditory Evoked Potential (BAEP. Methods & Material: The study was conducted in the clinical neurophysiology lab in the department of physiology, CSMMU Lucknow. Study group involved 26 subjects (n=26 having GBS and control group involved 30 normal subjects (n=30. BAEPS were recorded by Neuroperfect- EMG 2000 EMG/NCV/EPsytem. The data so obtained were subjected to analysis using Statistical Package for Social Sciences (SPSS Version 13.0. Results & Conclusions: There was significant increase in PIII & PV peak latencies and PI-PIII & PI-PV interpeak latencies in both left and right ear in the study group, which showed the CNS involvement in GBS which can be assessed using BAEP.

  13. Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

    Science.gov (United States)

    Abdullahi, Wazir; Davis, Thomas P; Ronaldson, Patrick T

    2017-07-01

    Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

  14. Management and Outcome of Patients With Langerhans Cell Histiocytosis and Single-Bone CNS-Risk Lesions: A Multi-Institutional Retrospective Study

    NARCIS (Netherlands)

    Chellapandian, Deepak; Shaikh, Furqan; van den Bos, Cor; Somers, Gino R.; Astigarraga, Itziar; Jubran, Rima; Degar, Barbara; Carret, Anne-Sophie; Mandel, Karen; Belletrutti, Mark; Dix, David; Visser, Johannes; Abuhadra, Nour; Chang, Tiffany; Rollins, Barret; Whitlock, James; Weitzman, Sheila; Abla, Oussama

    2015-01-01

    Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or

  15. The role of human endogenous retroviruses in brain development and function.

    Science.gov (United States)

    Mortelmans, Kristien; Wang-Johanning, Feng; Johanning, Gary L

    2016-01-01

    Endogenous retroviral sequences are spread throughout the genome of all humans, and make up about 8% of the genome. Despite their prevalence, the function of human endogenous retroviruses (HERVs) in humans is largely unknown. In this review we focus on the brain, and evaluate studies in animal models that address mechanisms of endogenous retrovirus activation in the brain and central nervous system (CNS). One such study in mice found that TRIM28, a protein critical for mouse early development, regulates transcription and silencing of endogenous retroviruses in neural progenitor cells. Another intriguing finding in human brain cells and mouse models was that endogenous retrovirus HERV-K appears to be protective against neurotoxins. We also report on studies that associate HERVs with human diseases of the brain and CNS. There is little doubt of an association between HERVs and a number of CNS diseases. However, a cause and effect relationship between HERVs and these diseases has not yet been established. © 2016 APMIS. Published by John Wiley & Sons Ltd.

  16. Genetic models for CNS inflammation

    DEFF Research Database (Denmark)

    Owens, T; Wekerle, H; Antel, J

    2001-01-01

    The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on ...

  17. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

    Science.gov (United States)

    Lafaille, Fabien G; Pessach, Itai M.; Zhang, Shen-Ying; Ciancanelli, Michael J.; Herman, Melina; Abhyankar, Avinash; Ying, Shui-Wang; Keros, Sotirios; Goldstein, Peter A.; Mostoslavsky, Gustavo; Ordovas-Montanes, Jose; Jouanguy, Emmanuelle; Plancoulaine, Sabine; Tu, Edmund; Elkabetz, Yechiel; Al-Muhsen, Saleh; Tardieu, Marc; Schlaeger, Thorsten M.; Daley, George Q.; Abel, Laurent; Casanova, Jean-Laurent; Studer, Lorenz; Notarangelo, Luigi D.

    2012-01-01

    In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies. PMID:23103873

  18. Mock-up tests on the combustion of hydrogen-air mixture in the vertical tube simulating the CNS channel of the CARR

    International Nuclear Information System (INIS)

    Yu Qingfeng; Feng Quanke; Kawai, Takeshi; Xu Jian

    2007-01-01

    A two-phase thermo-siphon loop for removing nuclear heating and maintaining the stable liquid level in the moderator cell was adopted for the cold neutron source (CNS) of the China advanced research reactor (CARR). The moderator is liquid hydrogen. The two-phase thermo-siphon loop consists of the crescent-shape moderator cell, the moderator transfer tube, and the condenser. The hydrogen is supplied from the buffer tank to the condenser. The main feature of the loop is that the moderator cell is covered by the helium sub-cooling system. The cold helium gas from the helium refrigerator is firstly introduced into the helium sub-cooling system and then flows up through the tube covering the moderator transfer tube into the condenser. The main part of this system is installed in the CNS vertical channel made of aluminum alloy 6061 T6 (Al-6061-T6) of 6 mm in thickness, 270 mm in outer diameter and about 6 m in height. For confirming the safety of the CNS channel, the combustion tests using a tube compatible with the CNS channel were carried out using the hydrogen-air mixture under which air is introduced into the tube at 1 atmosphere, and then hydrogen gas is supplied from the gas cylinder up to the test pressures. And maximum test pressure is 0.14 MPa G. This condition is involved with the maximum design basis accident of the CARR-CNS. The peak pressure due to combustion was 1.09 MPa, and the design pressure of the CNS channel is 3 MPa. The safety of the CNS was thus verified even if the maximum design basis accident occurs. The pressure and stress distributions along the axial direction and the displacement of the tube were also measured

  19. Analysis of NR3A receptor subunits in human native NMDA receptors

    DEFF Research Database (Denmark)

    Nilsson, Anna; Eriksson, Maria; Muly, E Chris

    2007-01-01

    NR3A, representing the third class of NMDA receptor subunits, was first studied in rats, demonstrating ubiquitous expression in the developing central nervous system (CNS), but in the adult mainly expressed in spinal cord and some forebrain nuclei. Subsequent studies showed that rodent and non-human...... primate NR3A expression differs. We have studied the distribution of NR3A in the human CNS and show a widespread distribution of NR3A protein in adult human brain. NR3A mRNA and protein were found in all regions of the cerebral cortex, and also in the subcortical forebrain, midbrain and hindbrain. Only...... very low levels of NR3A mRNA and protein could be detected in homogenized adult human spinal cord, and in situ hybridization showed that expression was limited to ventral motoneurons. We found that NR3A is associated with NR1, NR2A and NR2B in adult human CNS, suggesting the existence of native NR1-NR2...

  20. Lentiviral-mediated administration of IL-25 in the CNS induces alternative activation of microglia

    DEFF Research Database (Denmark)

    Maiorino, C; Khorooshi, R; Ruffini, F

    2013-01-01

    Interleukin-25 (IL-25) is the only anti-inflammatory cytokine of the IL-17 family, and it has been shown to be efficacious in inhibiting neuroinflammation. Known for its effects on cells of the adaptive immune system, it has been more recently described to be effective also on cells of the innate...... was partly inhibited and the CNS protected from immune-mediated damage. To our knowledge, this is the first example of M2 shift (alternative activation) induced in vivo on CNS-resident myeloid cells by gene therapy, and may constitute a promising strategy to investigate the potential role of protective...

  1. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS

    DEFF Research Database (Denmark)

    Reinert, Line S; Lopušná, Katarína; Winther, Henriette

    2016-01-01

    Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV-induced t......Herpes simplex encephalitis (HSE) is the most common form of acute viral encephalitis in industrialized countries. Type I interferon (IFN) is important for control of herpes simplex virus (HSV-1) in the central nervous system (CNS). Here we show that microglia are the main source of HSV......-induced type I IFN expression in CNS cells and these cytokines are induced in a cGAS-STING-dependent manner. Consistently, mice defective in cGAS or STING are highly susceptible to acute HSE. Although STING is redundant for cell-autonomous antiviral resistance in astrocytes and neurons, viral replication...... is strongly increased in neurons in STING-deficient mice. Interestingly, HSV-infected microglia confer STING-dependent antiviral activities in neurons and prime type I IFN production in astrocytes through the TLR3 pathway. Thus, sensing of HSV-1 infection in the CNS by microglia through the cGAS-STING pathway...

  2. Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

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    Andrea R. Yung

    2018-02-01

    Full Text Available During brainstem development, newborn neurons originating from the rhombic lip embark on exceptionally long migrations to generate nuclei important for audition, movement, and respiration. Along the way, this highly motile population passes several cranial nerves yet remains confined to the CNS. We found that Ntn1 accumulates beneath the pial surface separating the CNS from the PNS, with gaps at nerve entry sites. In mice null for Ntn1 or its receptor DCC, hindbrain neurons enter cranial nerves and migrate into the periphery. CNS neurons also escape when Ntn1 is selectively lost from the sub-pial region (SPR, and conversely, expression of Ntn1 throughout the mutant hindbrain can prevent their departure. These findings identify a permissive role for Ntn1 in maintaining the CNS-PNS boundary. We propose that Ntn1 confines rhombic lip-derived neurons by providing a preferred substrate for tangentially migrating neurons in the SPR, preventing their entry into nerve roots.

  3. Dynamic Simulation of Human Gait Model With Predictive Capability.

    Science.gov (United States)

    Sun, Jinming; Wu, Shaoli; Voglewede, Philip A

    2018-03-01

    In this paper, it is proposed that the central nervous system (CNS) controls human gait using a predictive control approach in conjunction with classical feedback control instead of exclusive classical feedback control theory that controls based on past error. To validate this proposition, a dynamic model of human gait is developed using a novel predictive approach to investigate the principles of the CNS. The model developed includes two parts: a plant model that represents the dynamics of human gait and a controller that represents the CNS. The plant model is a seven-segment, six-joint model that has nine degrees-of-freedom (DOF). The plant model is validated using data collected from able-bodied human subjects. The proposed controller utilizes model predictive control (MPC). MPC uses an internal model to predict the output in advance, compare the predicted output to the reference, and optimize the control input so that the predicted error is minimal. To decrease the complexity of the model, two joints are controlled using a proportional-derivative (PD) controller. The developed predictive human gait model is validated by simulating able-bodied human gait. The simulation results show that the developed model is able to simulate the kinematic output close to experimental data.

  4. Primary CNS lymphoma as a cause of Korsakoff syndrome.

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    Toth, Cory; Voll, Chris; Macaulay, Robert

    2002-01-01

    Korsakoff syndrome presents with memory dysfunction with retrograde amnesia, anterograde amnesia, limited insight into dysfunction, and confabulation. The most common etiology of Korsakoff syndrome is thiamine deficiency secondary to alcoholism. There are limited case reports of structural lesions causing Korsakoff syndrome. A 46-year-old male with a long history of alcoholism presented with a history of confusion, amnesia, and confabulation with no localizing features on neurological examination. The patient showed no clinical change with intravenous thiamine. Computed tomography of the brain revealed a heterogenous, enhancing mass lesion centered within the third ventricle, with other lesions found throughout cortical and subcortical regions. The patient was given dexamethasone i.v. without noticeable clinical improvement but with marked radiological improvement with mass reduction. Stereotactic biopsy revealed a diagnosis of primary central nervous system (CNS) lymphoma. Most patients presenting with Korsakoff syndrome have thiamine deficiency; however, mass lesions can produce an identical clinical picture. This is the first case report of a patient with primary CNS lymphoma presenting as Korsakoff syndrome.

  5. Adverse CNS-effects of beta-adrenoceptor blockers.

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    Gleiter, C H; Deckert, J

    1996-11-01

    In 1962 propranolol, the first beta adrenoceptor antagonist (beta blocker), was brought on to the market. There is now a host of different beta blockers available, and these compounds are among the most commonly prescribed groups of drugs. The efficacy of beta blockers has been proven predominantly for the treatment of cardiovascular diseases. Beta blockers are also used for certain types of CNS disorders, such as anxiety disorders, essential tremor and migraine. While low toxicity means that they have a favorable risk-benefit ratio, given the high intensity of use, it is essential to have a comprehensive knowledge of adverse events. Adverse events of beta blockers that can be related to the CNS are quite often neglected, even in textbooks of clinical pharmacology or review articles, and thus often misdiagnosed. The following article, therefore, after summarizing the use of beta blockers for CNS indications, critically reviews the literature on centrally mediated adverse events. General pharmacological features of beta blockers and their molecular basis of action will briefly be addressed to the extent that they are or may become relevant for central nervous pharmacotherapy and side-effects.

  6. Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Espejo, C; Carrasco, J; Hidalgo, J

    2001-01-01

    Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein......-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression...

  7. Cleavage of a Neuroinvasive Human Respiratory Virus Spike Glycoprotein by Proprotein Convertases Modulates Neurovirulence and Virus Spread within the Central Nervous System.

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    Alain Le Coupanec

    Full Text Available Human coronaviruses (HCoV are respiratory pathogens that may be associated with the development of neurological diseases, in view of their neuroinvasive and neurotropic properties. The viral spike (S glycoprotein is a major virulence factor for several coronavirus species, including the OC43 strain of HCoV (HCoV-OC43. In an attempt to study the role of this protein in virus spread within the central nervous system (CNS and neurovirulence, as well as to identify amino acid residues important for such functions, we compared the sequence of the S gene found in the laboratory reference strain HCoV-OC43 ATCC VR-759 to S sequences of viruses detected in clinical isolates from the human respiratory tract. We identified one predominant mutation at amino acid 758 (from RRSR↓ G758 to RRSR↓R758, which introduces a putative furin-like cleavage (↓ site. Using a molecular cDNA infectious clone to generate a corresponding recombinant virus, we show for the first time that such point mutation in the HCoV-OC43 S glycoprotein creates a functional cleavage site between the S1 and S2 portions of the S protein. While the corresponding recombinant virus retained its neuroinvasive properties, this mutation led to decreased neurovirulence while potentially modifying the mode of virus spread, likely leading to a limited dissemination within the CNS. Taken together, these results are consistent with the adaptation of HCoV-OC43 to the CNS environment, resulting from the selection of quasi-species harboring mutations that lead to amino acid changes in viral genes, like the S gene in HCoV-OC43, which may contribute to a more efficient establishment of a less pathogenic but persistent CNS infection. This adaptative mechanism could potentially be associated with human encephalitis or other neurological degenerative pathologies.

  8. Fluid Induced Vibration Analysis of a Cooling Water Pipeline for the HANARO CNS

    International Nuclear Information System (INIS)

    Kim, Bong Soo; Lee, Young Sub; Kim, Ik Soo; Kim, Young Ki

    2007-01-01

    CNS is the initial of Cold Neutron Source and the CNS facility system consists of hydrogen, a vacuum, a gas blanketing, a helium refrigeration and a cooling water supply system. Out of these subsystems, the helium refrigeration system has the function of removal of heat from a thermal neutron under reactor operation. Therefore, HRS (helium refrigeration system) must be under normal operation for the production of cold neutron. HRS is mainly made up of a helium compressor and a coldbox. This equipment is in need of cooling water to get rid of heat generation under stable operation and a cooling water system is essential to maintain the normal operation of a helium compressor and a coldbox. The main problem for the cooling water system is the vibration issue in the middle of operation due to a water flow in a pipeline. In order to suppress the vibration problem for a pipeline, the characteristics of a pipeline and fluid flow must be analyzed in detail. In this paper, fluid induced vibration of a cooling water pipe is analyzed numerically and the stability of the cooling water pipeline is investigated by using pipe dynamic theory

  9. Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.

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    Roberta Noseda

    2016-04-01

    Full Text Available Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS and central nervous system (CNS myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1, a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K/v-AKT murine thymoma viral oncogene homolog (AKT pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.

  10. Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination

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    Alerie Guzman De La Fuente

    2017-08-01

    Full Text Available The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfbret/ret mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  11. Neuropharmacology of Human Appetite Expression

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    Halford, Jason C. G.; Harrold, Joanne A.

    2008-01-01

    The regulation of appetite relies on the integration of numerous episodic (meal) and tonic (energy storage) generated signals in energy regulatory centres within the central nervous system (CNS). These centers provide the pharmacological potential to modify human appetite (hunger and satiety) to increase or decrease caloric intake, or to normalize…

  12. A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

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    Romeo Cecchelli

    Full Text Available The human blood brain barrier (BBB is a selective barrier formed by human brain endothelial cells (hBECs, which is important to ensure adequate neuronal function and protect the central nervous system (CNS from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

  13. Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report.

    Science.gov (United States)

    Kirkman, Matthew A; Pickles, Jessica C; Fairchild, Amy R; Avery, Aimee; Pietsch, Torsten; Jacques, Thomas S; Aquilina, Kristian

    2018-05-30

    Advances in molecular profiling have facilitated the emergence of newly defined entities of central nervous system tumor, including CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Relatively little is known about the clinical behaviour of these newly-characterized tumors. We describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor. This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques. Copyright © 2018. Published by Elsevier Inc.

  14. Direct exposure of guinea pig CNS to human luteinizing hormone increases cerebrospinal fluid and cerebral beta amyloid levels.

    Science.gov (United States)

    Wahjoepramono, Eka J; Wijaya, Linda K; Taddei, Kevin; Bates, Kristyn A; Howard, Matthew; Martins, Georgia; deRuyck, Karl; Matthews, Paul M; Verdile, Giuseppe; Martins, Ralph N

    2011-01-01

    Luteinizing hormone (LH) has been shown to alter the metabolism of beta amyloid (Aβ), a key protein in Alzheimer's disease (AD) pathogenesis. While LH and components required for LH receptor signalling are present in the brain, their role in the CNS remains unclear. In vitro, LH has been shown to facilitate neurosteroid production and alter Aβ metabolism. However, whether LH can directly modulate cerebral Aβ levels in vivo has not previously been studied. In this study, we investigated the effect of chronic administration of LH to the guinea pig CNS on cerebral Aβ levels. Gonadectomised male animals were administered, via cortical placement, either placebo or LH slow-release pellets. At 14 and 28 days after treatment, animals were sacrificed. Brain, plasma and CSF were collected and Aβ levels measured via ELISA. Levels of the Aβ precursor protein (APP) and the neurosteroidogenic enzyme cytochrome P450 side-chain cleavage enzyme (P450scc) were also assayed. An increase in CSF Aβ40 levels was observed 28 days following treatment. These CSF data also reflected changes in Aβ40 levels observed in brain homogenates. No change was observed in plasma Aβ40 levels but APP and its C-terminal fragments (APP-CTF) were significantly increased in response to LH exposure. Protein expression of P450scc was increased after 28 days of LH exposure, suggesting activation of the LH receptor. These data indicate that direct exposure of guinea pig CNS to LH results in altered brain Aβ levels, perhaps due to altered APP expression/metabolism. Copyright © 2011 S. Karger AG, Basel.

  15. Region-specific vulnerability to lipid peroxidation and evidence of neuronal mechanisms for polyunsaturated fatty acid biosynthesis in the healthy adult human central nervous system.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Dominguez-Gonzalez, Mayelin; Ayala, Victoria; Jové, Mariona; Mota-Martorell, Natalia; Piñol-Ripoll, Gerard; Gil-Villar, Maria Pilar; Rué, Montserrat; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2017-05-01

    Lipids played a determinant role in the evolution of the brain. It is postulated that the morphological and functional diversity among neural cells of the human central nervous system (CNS) is projected and achieved through the expression of particular lipid profiles. The present study was designed to evaluate the differential vulnerability to oxidative stress mediated by lipids through a cross-regional comparative approach. To this end, we compared 12 different regions of CNS of healthy adult subjects, and the fatty acid profile and vulnerability to lipid peroxidation, were determined by gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS), respectively. In addition, different components involved in PUFA biosynthesis, as well as adaptive defense mechanisms against lipid peroxidation, were also measured by western blot and immunohistochemistry, respectively. We found that: i) four fatty acids (18.1n-9, 22:6n-3, 20:1n-9, and 18:0) are significant discriminators among CNS regions; ii) these differential fatty acid profiles generate a differential selective neural vulnerability (expressed by the peroxidizability index); iii) the cross-regional differences for the fatty acid profiles follow a caudal-cranial gradient which is directly related to changes in the biosynthesis pathways which can be ascribed to neuronal cells; and iv) the higher the peroxidizability index for a given human brain region, the lower concentration of the protein damage markers, likely supported by the presence of adaptive antioxidant mechanisms. In conclusion, our results suggest that there is a region-specific vulnerability to lipid peroxidation and offer evidence of neuronal mechanisms for polyunsaturated fatty acid biosynthesis in the human central nervous system. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Problems of prophylactic CNS radiotherapy in acute children's leukemia

    International Nuclear Information System (INIS)

    Bek, V.; Pribylova, O.; Abrahamova, J.; Hynieova, H.; Hrodek, O.

    1980-01-01

    The prophylactic treatment of the CNS was conducted by cobalt teletherapy of the cranium and by intrathecal application of MTX after the induction of primary remission in 70 children with acute leukemia throughout 5 years up to the end of 1978. The method of the combined radio- and chemoprophylaxis of the CNS was being changed during the years, especially as far as the radiation dose for the cranium was concerned. A detailed analysis made in a group of 59 children with the minimum interval of 18 months from the beginning of the treatment showed the best results after the application of a dose of 24 Gy/3 weeks. Following this procedure the relapse of leukemia in the CNS occurred in 9% only, whereas on the application of doses of 20 Gy and lower it occurred in 35 to 40%. On the whole 24 out of 59 children, i.e. 41%, are surviving, 35 children, i.e. 59%, died. Mostly complete, but only temporary, epilation was an invariable consequence of the irradiation of the cranium. The somnolence syndrome was only sporadically observed. It cannot be excluded, however, that some of its forms in patients discharged from hospital escaped attention. No case was recorded of serious impairment of the CNS of the leukoencephalopathic type. Up to now the psychomotor, intellectual and emotional development of the surviving children has been normal. (author)

  17. P13.10 Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases

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    Yust-Katz, S.; Dudnik, E.; Perlov, E.; Zer, A.; Flex, D.; Peled, N.; Siegal, T.

    2016-01-01

    Abstract Background: Central nervous system (CNS) metastases occur in about 30% of patients (pts) with advanced non-small cell lung cancer (NSCLC). Local treatment strategies (e.g., radiotherapy or surgery) result in delays in systemic therapy administration and are frequently associated with neurocognitive impairment. Nivolumab is an anti-PD1 immune check-point inhibitor which has been recently approved by the FDA as a second line treatment of NSCLC. Data regarding its intracranial activity is lacking. Methods: We retrospectively reviewed efficacy and safety of nivolumab administered intravenously at a dose of 3mg/kg q2 weeks in five pts with advanced NSCLC and new or progressing intracranial metastases which were diagnosed before or within 1 month after starting the treatment. Results: Pt baseline characteristics were as follows: median age 78y (range, 52–84); 2 males; 4 smokers; ECOG PS 0/1/2 - 2 pts/1 pt/2 pts; histological subtype: adenocarcinoma/ squamous-cell carcinoma/NSCLC NOS 3 pts /1 pt/1 pt; EGFR WT/ALK neg/KRAS M all/all/2 pts. Four pts had parenchymal brain metastases, three pts had leptomeningeal disease. All pts were asymptomatic and did not require corticosteroids or immediate brain irradiation. Dramatic response in the brain was observed in two pts (including 1 pt with leptomeningeal spread demonstrating a complete response in the CNS); time-to-response comprised 5 weeks and 9 weeks; all responses are still ongoing at the time of the report (18+ weeks, 19+ weeks). In one pt stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved. Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS-metastases related grade ≥ 3 adverse events were observed. Conclusions: Nivolumab has a promising intracranial activity and favorable safety profile in pts with NSCLC and untreated/progressing CNS metastases. Nivolumab CNS activity warrants further evaluation.

  18. Dual DNA methylation patterns in the CNS reveal developmentally poised chromatin and monoallelic expression of critical genes.

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    Jinhui Wang

    Full Text Available As a first step towards discovery of genes expressed from only one allele in the CNS, we used a tiling array assay for DNA sequences that are both methylated and unmethylated (the MAUD assay. We analyzed regulatory regions of the entire mouse brain transcriptome, and found that approximately 10% of the genes assayed showed dual DNA methylation patterns. They include a large subset of genes that display marks of both active and silent, i.e., poised, chromatin during development, consistent with a link between differential DNA methylation and lineage-specific differentiation within the CNS. Sixty-five of the MAUD hits and 57 other genes whose function is of relevance to CNS development and/or disorders were tested for allele-specific expression in F(1 hybrid clonal neural stem cell (NSC lines. Eight MAUD hits and one additional gene showed such expression. They include Lgi1, which causes a subtype of inherited epilepsy that displays autosomal dominance with incomplete penetrance; Gfra2, a receptor for glial cell line-derived neurotrophic factor GDNF that has been linked to kindling epilepsy; Unc5a, a netrin-1 receptor important in neurodevelopment; and Cspg4, a membrane chondroitin sulfate proteoglycan associated with malignant melanoma and astrocytoma in human. Three of the genes, Camk2a, Kcnc4, and Unc5a, show preferential expression of the same allele in all clonal NSC lines tested. The other six genes show a stochastic pattern of monoallelic expression in some NSC lines and bi-allelic expression in others. These results support the estimate that 1-2% of genes expressed in the CNS may be subject to allelic exclusion, and demonstrate that the group includes genes implicated in major disorders of the CNS as well as neurodevelopment.

  19. Acute central nervous system (CNS) toxicity of total body irradiation (TBI) measured using neuropsychological testing of attention functions

    International Nuclear Information System (INIS)

    Wenz, Frederik; Steinvorth, Sarah; Lohr, Frank; Hacke, Werner; Wannenmacher, Michael

    1999-01-01

    Purpose: The purpose of this study was to investigate acute normal tissue damage of low irradiation doses to the healthy, adult central nervous system (CNS) using neuropsychological testing of attention functions. Methods and Materials: Neuropsychological testing (IQ, attention [modified Trail-Making Test A, Digit Symbol Test, D2 Test, Wiener Determination Machine]) was used to examine 40 patients (43 ± 10 years) before and immediately after the first fraction (1.2 Gy) of hyperfractionated total body irradiation (TBI) at the University of Heidelberg. The patients received antiemetic premedication. Test results are given as mean percentiles ± standard deviation, with 50 ± 34 being normal. Thirty-eight control patients (53 ± 15 years) were studied to quantify the influence of hospitalization, stress, and repeated testing. Results: The patients showed normal baseline test results (IQ = 101 ± 14, attention = 54 ± 28) and no decrease in test results after 1.2 Gy TBI. Attention functions improved (66 ± 25) corresponding to a practice effect of repeated testing that was seen in the control group, although alternate versions of the tests were used (IQ = 104 ± 10, attention before = 42 ± 29, attention after = 52 ± 31). Conclusion: Our data show no deterioration of neuropsychologic test results acutely after 1.2 Gy whole body exposure in adult patients without CNS disease receiving antiemetic medication

  20. CNS metastasis from malignant uveal melanoma: a clinical and histopathological characterisation

    DEFF Research Database (Denmark)

    Holfort, S K; Lindegaard, J; Isager, P

    2008-01-01

    was observed in two cases (14%). The amount of tumour infiltrating lymphocytes was pronounced in three cases (23%). CONCLUSION: The proportion of uveal melanoma patients having CNS metastasis was 0.7%. Eleven patients had multiple organ metastases, and the average time from the initial CNS symptoms to death...

  1. Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease.

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    Mario A Cabrera-Salazar

    Full Text Available Neuropathic Gaucher disease (nGD, also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC. This deficiency impairs the degradation of glucosylceramide (GluCer and glucosylsphingosine (GluSph, leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.

  2. Systemic delivery of a glucosylceramide synthase inhibitor reduces CNS substrates and increases lifespan in a mouse model of type 2 Gaucher disease.

    Science.gov (United States)

    Cabrera-Salazar, Mario A; Deriso, Matthew; Bercury, Scott D; Li, Lingyun; Lydon, John T; Weber, William; Pande, Nilesh; Cromwell, Mandy A; Copeland, Diane; Leonard, John; Cheng, Seng H; Scheule, Ronald K

    2012-01-01

    Neuropathic Gaucher disease (nGD), also known as type 2 or type 3 Gaucher disease, is caused by a deficiency of the enzyme glucocerebrosidase (GC). This deficiency impairs the degradation of glucosylceramide (GluCer) and glucosylsphingosine (GluSph), leading to their accumulation in the brains of patients and mouse models of the disease. These accumulated substrates have been thought to cause the severe neuropathology and early death observed in patients with nGD and mouse models. Substrate accumulation is evident at birth in both nGD mouse models and humans affected with the most severe type of the disease. Current treatment of non-nGD relies on the intravenous delivery of recombinant human glucocerebrosidase to replace the missing enzyme or the administration of glucosylceramide synthase inhibitors to attenuate GluCer production. However, the currently approved drugs that use these mechanisms do not cross the blood brain barrier, and thus are not expected to provide a benefit for the neurological complications in nGD patients. Here we report the successful reduction of substrate accumulation and CNS pathology together with a significant increase in lifespan after systemic administration of a novel glucosylceramide synthase inhibitor to a mouse model of nGD. To our knowledge this is the first compound shown to cross the blood brain barrier and reduce substrates in this animal model while significantly enhancing its lifespan. These results reinforce the concept that systemically administered glucosylceramide synthase inhibitors could hold enhanced therapeutic promise for patients afflicted with neuropathic lysosomal storage diseases.

  3. SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury

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    Emma V. Jones

    2018-02-01

    Full Text Available The proper formation and maintenance of functional synapses in the central nervous system (CNS requires communication between neurons and astrocytes and the ability of astrocytes to release neuromodulatory molecules. Previously, we described a novel role for the astrocyte-secreted matricellular protein SPARC (Secreted Protein, Acidic and Rich in Cysteine in regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs and plasticity at developing synapses. SPARC is highly expressed by astrocytes and microglia during CNS development but its level is reduced in adulthood. Interestingly, SPARC has been shown to be upregulated in CNS injury and disease. However, the role of SPARC upregulation in these contexts is not fully understood. In this study, we investigated the effect of chronic SPARC administration on glutamate receptors on mature hippocampal neuron cultures and following CNS injury. We found that SPARC treatment increased the number of GluA1-containing AMPARs at synapses and enhanced synaptic function. Furthermore, we determined that the increase in synaptic strength induced by SPARC could be inhibited by Philanthotoxin-433, a blocker of homomeric GluA1-containing AMPARs. We then investigated the effect of SPARC treatment on neuronal health in an injury context where SPARC expression is upregulated. We found that SPARC levels are increased in astrocytes and microglia following middle cerebral artery occlusion (MCAO in vivo and oxygen-glucose deprivation (OGD in vitro. Remarkably, chronic pre-treatment with SPARC prevented OGD-induced loss of synaptic GluA1. Furthermore, SPARC treatment reduced neuronal death through Philanthotoxin-433 sensitive GluA1 receptors. Taken together, this study suggests a novel role for SPARC and GluA1 in promoting neuronal health and recovery following CNS damage.

  4. EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells

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    Florian Wanke

    2017-01-01

    Full Text Available Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE, the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23 and interleukin-1 beta (IL-1β, maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.

  5. The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity

    International Nuclear Information System (INIS)

    Zhou Naiming; Zhang Xiaoling; Fan Xuejun; Argyris, Elias; Fang Jianhua; Acheampong, Edward; DuBois, Garrett C.; Pomerantz, Roger J.

    2003-01-01

    The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS

  6. Direct and Systemic Administration of a CNS-Permeant Tamoxifen Analog Reduces Amphetamine-Induced Dopamine Release and Reinforcing Effects.

    Science.gov (United States)

    Carpenter, Colleen; Zestos, Alexander G; Altshuler, Rachel; Sorenson, Roderick J; Guptaroy, Bipasha; Showalter, Hollis D; Kennedy, Robert T; Jutkiewicz, Emily; Gnegy, Margaret E

    2017-09-01

    Amphetamines (AMPHs) are globally abused. With no effective treatment for AMPH addiction to date, there is urgent need for the identification of druggable targets that mediate the reinforcing action of this stimulant class. AMPH-stimulated dopamine efflux is modulated by protein kinase C (PKC) activation. Inhibition of PKC reduces AMPH-stimulated dopamine efflux and locomotor activity. The only known CNS-permeant PKC inhibitor is the selective estrogen receptor modulator tamoxifen. In this study, we demonstrate that a tamoxifen analog, 6c, which more potently inhibits PKC than tamoxifen but lacks affinity for the estrogen receptor, reduces AMPH-stimulated increases in extracellular dopamine and reinforcement-related behavior. In rat striatal synaptosomes, 6c was almost fivefold more potent at inhibiting AMPH-stimulated dopamine efflux than [ 3 H]dopamine uptake through the dopamine transporter (DAT). The compound did not compete with [ 3 H]WIN 35,428 binding or affect surface DAT levels. Using microdialysis, direct accumbal administration of 1 μM 6c reduced dopamine overflow in freely moving rats. Using LC-MS, we demonstrate that 6c is CNS-permeant. Systemic treatment of rats with 6 mg/kg 6c either simultaneously or 18 h prior to systemic AMPH administration reduced both AMPH-stimulated dopamine overflow and AMPH-induced locomotor effects. Finally, 18 h pretreatment of rats with 6 mg/kg 6c s.c. reduces AMPH-self administration but not food self-administration. These results demonstrate the utility of tamoxifen analogs in reducing AMPH effects on dopamine and reinforcement-related behaviors and suggest a new avenue of development for therapeutics to reduce AMPH abuse.

  7. Effects of prolonged treatment with memantine in the MRL model of CNS lupus.

    Science.gov (United States)

    Marcinko, Katarina; Parsons, Tiffany; Lerch, Jason P; Sled, John G; Sakic, Boris

    2012-09-01

    Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

  8. Dose-dense chemoimmunotherapy and CNS prophylaxis in patients with high-risk DLBCL: a comparison of Nordic CRY-04 and CHIC studies

    DEFF Research Database (Denmark)

    Leppä, Sirpa; Jørgensen, Judit Meszaros; Brown, Peter De Nully

    Background: Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two completed Nordic trials...... including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these studies to compare clinical outcome and prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) vs at the end (CRY-04) of therapy. Patients and methods: Inclusion...... proliferation index (Ki67 expression available PET data, Deauville score 5 at the end of treatment was associated with increased rate of progression and death in both trials (p=0.012). Only one out of 17 biopsies from PET positive...

  9. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

    Science.gov (United States)

    Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

    2017-08-08

    The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Foxp3+ regulatory T cells control persistence of viral CNS infection.

    Directory of Open Access Journals (Sweden)

    Dajana Reuter

    Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

  11. Management of CNS tumors

    International Nuclear Information System (INIS)

    Griem, M.L.

    1987-01-01

    The treatment of tumors of the CNS has undergone a number of changes based on the impact of CT. The use of intraoperative US for the establishment of tumor location and tumor histology is demonstrated. MR imaging also is beginning to make an impact on the diagnosis and treatment of tumors of the CNS. Examples of MR images are shown. The authors then discuss the important aspects of tumor histology as it affects management and newer concepts in surgery, radiation, and chemotherapy on tumor treatment. The role of intraoperative placement of radioactive sources, the utilization of heavy particle radiation therapy, and the potential role of other experimental radiation therapy techniques are discussed. The role of hyperfractionated radiation and of neutrons and x-ray in a mixed-beam treatment are discussed in perspective with standard radiation therapy. Current chemotherapy techniques, including intraarterial chemotherapy, are discussed. The complications of radiation therapy alone and in combination with chemotherapy in the management of primary brain tumors, brain metastases, and leukemia are reviewed. A summary of the current management of pituitary tumors, including secreting pituitary adenomas and chromophobe adenomas, are discussed. The treatment with heavy particle radiation, transsphenoidal microsurgical removal, and combined radiotherapeutic and surgical management are considered. Tumor metastasis management of lesions of the brain and spinal cord are considered

  12. Observation and quantitative analyses of the skeletal and central nervous systems of human embryos and fetuses using microimaging techniques

    International Nuclear Information System (INIS)

    Shiota, Kohei; Yamada, Shigehito; Tsuchiya, Maiko; Nakajima, Takashi; Takakuwa, Tetsuya; Morimoto, Naoki; Ogihara, Naomichi; Katayama, Kazumichi; Kose, Katsumi

    2011-01-01

    High resolution images have been available to trace the organogenesis of the central nervous system (CNS) and crania of human embryo and fetus with microimaging techniques of CT, novel MR microscopy and episcopic fluorescence image capture (EFIC). The helical CT was conducted for Kyoto University's stock specimens of 31 fetuses at gestational stages 8-24 weeks to observe the skeletal development of neuro- and viscero-cranium in 2D and 3D view. Sixty seven landmarks were defined on the images at outer surface and lumen of the skull to analyze the morphological development. Increase of cranial length was found significant relative to width and height in fetus, confirming the faster development of neurocranium than viscero-region. Next, 1.5/2.34 T MR microscopic imaging was conducted for fixed specimens of >1000 embryos at 4-8 weeks after fertilization. For this, a newly developed contrast optimization by mapping the specimen with the relaxation time had been performed to acquire the highest resolution in the world of 80-120 micrometer, which enabled to image primordia of the inner embryonic structures like brain, spinal cord, choroid plexus, skeletons of skull and spinal column. The finding was thought helpful for analysis and diagnosis of their early development. EFIC of embryos was conducted firstly in the world, where spontaneous fluorescence of their cross section was captured by the fluorescent microscope with the resolution as high as <10 micrometer to reconstruct 2D/3D images. EFIC was found to give images of embryonic CNS, ventricular system, layering structures of brain and spinal cord without staining, and to give sequential changes of their volumes quantitated during the development. The reported microimaging techniques were concluded useful for analysis of normal and abnormal early development of CNS and skull in humans. (T.T.)

  13. Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

    Directory of Open Access Journals (Sweden)

    Bartholomew J Naughton

    Full Text Available Mucopolysaccharidosis (MPS IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.

  14. Palmitoylethanolamide in CNS health and disease.

    Science.gov (United States)

    Mattace Raso, Giuseppina; Russo, Roberto; Calignano, Antonio; Meli, Rosaria

    2014-08-01

    The existence of acylethanolamides (AEs) in the mammalian brain has been known for decades. Among AEs, palmitoylethanolamide (PEA) is abundant in the central nervous system (CNS) and conspicuously produced by neurons and glial cells. Antihyperalgesic and neuroprotective properties of PEA have been mainly related to the reduction of neuronal firing and to control of inflammation. Growing evidence suggest that PEA may be neuroprotective during CNS neurodegenerative diseases. Advances in the understanding of the physiology and pharmacology of PEA have potentiated its interest as useful biological tool for disease management. Several rapid non-genomic and delayed genomic mechanisms of action have been identified for PEA as peroxisome proliferator-activated receptor (PPAR)-α dependent. First, an early molecular control, through Ca(+2)-activated intermediate- and/or big-conductance K(+) channels opening, drives to rapid neuronal hyperpolarization. This is reinforced by the increase of the inward Cl(-) currents due to the modulation of the gamma aminobutyric acid A receptor and by the desensitization of the transient receptor potential channel type V1. Moreover, the gene transcription-mediated mechanism sustains the long-term anti-inflammatory effects, by reducing pro-inflammatory enzyme expression and increasing neurosteroid synthesis. Overall, the integration of these different modes of action allows PEA to exert an immediate and prolonged efficacious control in neuron signaling either on inflammatory process or neuronal excitability, maintaining cellular homeostasis. In this review, we will discuss the effect of PEA on metabolism, behavior, inflammation and pain perception, related to the control of central functions and the emerging evidence demonstrating its therapeutic efficacy in several neurodegenerative diseases. Copyright © 2014. Published by Elsevier Ltd.

  15. Gut-derived factors promote neurogenesis of CNS-neural stem cells and nudge their differentiation to an enteric-like neuronal phenotype.

    Science.gov (United States)

    Kulkarni, Subhash; Zou, Bende; Hanson, Jesse; Micci, Maria-Adelaide; Tiwari, Gunjan; Becker, Laren; Kaiser, Martin; Xie, Xinmin Simon; Pasricha, Pankaj Jay

    2011-10-01

    Recent studies have explored the potential of central nervous system-derived neural stem cells (CNS-NSC) to repopulate the enteric nervous system. However, the exact phenotypic fate of gut-transplanted CNS-NSC has not been characterized. The aim of this study was to investigate the effect of the gut microenvironment on phenotypic fate of CNS-NSC in vitro. With the use of Transwell culture, differentiation of mouse embryonic CNS-NSC was studied when cocultured without direct contact with mouse intestinal longitudinal muscle-myenteric plexus preparations (LM-MP) compared with control noncocultured cells, in a differentiating medium. Differentiated cells were analyzed by immunocytochemistry and quantitative RT-PCR to assess the expression of specific markers and by whole cell patch-clamp studies for functional characterization of their phenotype. We found that LM-MP cocultured cells had a significant increase in the numbers of cells that were immune reactive against the panneuronal marker β-tubulin, neurotransmitters neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and neuropeptide vasoactive intestinal peptide (VIP) and showed an increase in expression of these genes, compared with control cells. Whole cell patch-clamp analysis showed that coculture with LM-MP decreases cell excitability and reduces voltage-gated Na(+) currents but significantly enhances A-current and late afterhyperpolarization (AHP) and increases the expression of the four AHP-generating Ca(2+)-dependent K(+) channel genes (KCNN), compared with control cells. In a separate experiment, differentiation of LM-MP cocultured CNS-NSC produced a significant increase in the numbers of cells that were immune reactive against the neurotransmitters nNOS, ChAT, and the neuropeptide VIP compared with CNS-NSC differentiated similarly in the presence of neonatal brain tissue. Our results show that the gut microenvironment induces CNS-NSC to produce neurons that share some of the

  16. Physical attraction to reliable, low variability nervous systems: Reaction time variability predicts attractiveness.

    Science.gov (United States)

    Butler, Emily E; Saville, Christopher W N; Ward, Robert; Ramsey, Richard

    2017-01-01

    The human face cues a range of important fitness information, which guides mate selection towards desirable others. Given humans' high investment in the central nervous system (CNS), cues to CNS function should be especially important in social selection. We tested if facial attractiveness preferences are sensitive to the reliability of human nervous system function. Several decades of research suggest an operational measure for CNS reliability is reaction time variability, which is measured by standard deviation of reaction times across trials. Across two experiments, we show that low reaction time variability is associated with facial attractiveness. Moreover, variability in performance made a unique contribution to attractiveness judgements above and beyond both physical health and sex-typicality judgements, which have previously been associated with perceptions of attractiveness. In a third experiment, we empirically estimated the distribution of attractiveness preferences expected by chance and show that the size and direction of our results in Experiments 1 and 2 are statistically unlikely without reference to reaction time variability. We conclude that an operating characteristic of the human nervous system, reliability of information processing, is signalled to others through facial appearance. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Evaluation of calcium, magnesium, zinc, aluminum and manganese deposition in bones and CNS of rats fed calcium-deficient diets

    International Nuclear Information System (INIS)

    Yasui, Masayuki; Ota, Kiichiro; Sasajima, Kazuhisa; Iwata, Shiro.

    1994-01-01

    The long term intake of unbalanced mineral diets has been reported to be one of the pathogenetic factors of central nervous system (CNS) degeneration, and the unbalanced mineral distribution in the bones clinically is expressed as a metabolic bone disorder or deposition of neurotoxic minerals/metals. The unbalanced mineral or metal diets in animals provoke the unbalanced mineral distribution in bones and soft tissues. In this study, the calcium (Ca), magnesium (Mg), zinc (Zn), aluminum (Al) and manganese (Mn) contents in the CNS and the bones of rats maintained on unbalanced mineral diets were analyzed to investigate the roles of bone on CNS degeneration. Male Wistar rats were maintained for 90 days on the following diets: (A) standard diet, (B) low Ca diet, (C) low Ca-Mg diet, (D) low Ca-Mg diet with high Al. Al and Mn contents were determined in the frontal cortex, spinal cord, lumbar spine and femur using inductively coupled plasma emission spectrometry (ICP) for Ca, Mg and Zn, and neutron activation analysis (NAA) for Al and Mn. Intake of low Ca and Mg with added Al in rats led to the abnormal distribution of metals or minerals in the bones and in the CNS. These results illustrate that unbalanced mineral diets and metal-metal interactions may lead to the irregular deposition of Al and Mn in the bones and ultimately in the CNS, thus inducing CNS degeneration. (author)

  18. The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system?

    Science.gov (United States)

    Abbott, N Joan; Pizzo, Michelle E; Preston, Jane E; Janigro, Damir; Thorne, Robert G

    2018-03-01

    Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with

  19. Developmental hyperoxia alters CNS mechanisms underlying hypoxic ventilatory depression in neonatal rats.

    Science.gov (United States)

    Hill, Corey B; Grandgeorge, Samuel H; Bavis, Ryan W

    2013-12-01

    Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR), but the relative contributions of carotid body-initiated CNS mechanisms versus central hypoxia on ventilatory depression during the late phase of the HVR are not well understood. Neonatal rats (P4-5 or P13-15) were treated with a nonselective P2 purinergic receptor antagonist (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, or PPADS; 125mgkg(-1), i.p.) to pharmacologically denervate the peripheral chemoreceptors. At P4-5, rats reared in normoxia showed a progressive decline in ventilation during a 10-min exposure to 12% O2 (21-28% decrease from baseline). No hypoxic ventilatory depression was observed in the older group of neonatal rats (i.e., P13-15), suggesting that the contribution of central hypoxia to hypoxic ventilatory depression diminishes with age. In contrast, rats reared in moderate hyperoxia (60% O2) from birth exhibited no hypoxic ventilatory depression at either age studied. Systemic PPADS had no effect on the ventilatory response to 7% CO2, suggesting that the drug did not cross the blood-brain barrier. These findings indicate that (1) CNS hypoxia depresses ventilation in young, neonatal rats independent of carotid body activation and (2) hyperoxia alters the development of CNS pathways that modulate the late phase of the hypoxic ventilatory response. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Durable treatment response of relapsing CNS plasmacytoma using intrathecal chemotherapy, radiotherapy, and Daratumumab.

    Science.gov (United States)

    Elhassadi, Ezzat; Murphy, Maurice; Hacking, Dayle; Farrell, Michael

    2018-04-01

    CNS myelomatous involvement is a rare complication of multiple myeloma with dismal outcome. This disease's optimal treatment is unclear. Combined approach of systemic therapy, radiotherapy, and intrathecal injections chemotherapy should be considered and autologous stem cell transplant consolidation is offered to eligible patients. The role of Daratumumab in this disease deserves further evaluation.

  1. Meningitis Caused by Toscana Virus Is Associated with Strong Antiviral Response in the CNS and Altered Frequency of Blood Antigen-Presenting Cells

    Directory of Open Access Journals (Sweden)

    Stefania Varani

    2015-11-01

    Full Text Available Toscana virus (TOSV is a Phlebotomus-transmitted RNA virus and a frequent cause of human meningitis and meningoencephalitis in Southern Europe during the summer season. While evidence for TOSV-related central nervous system (CNS cases is increasing, little is known about the host defenses against TOSV. We evaluated innate immune response to TOSV by analyzing frequency and activation of blood antigen-presenting cells (APCs and cytokine levels in plasma and cerebrospinal fluid (CSF from patients with TOSV neuroinvasive infection and controls. An altered frequency of different blood APC subsets was observed in TOSV-infected patients, with signs of monocytic deactivation. Nevertheless, a proper or even increased responsiveness of toll-like receptor 3 and 7/8 was observed in blood APCs of these patients as compared to healthy controls. Systemic levels of cytokines remained low in TOSV-infected patients, while levels of anti-inflammatory and antiviral mediators were significantly higher in CSF from TOSV-infected patients as compared to patients with other infectious and noninfectious neurological diseases. Thus, the early host response to TOSV appears effective for viral clearance, by proper response to TLR3 and TLR7/8 agonists in peripheral blood and by a strong and selective antiviral and anti-inflammatory response in the CNS.

  2. Targeting α4β2 nAChRs in CNS disorders: Perspectives on positive allosteric modulation as a therapeutic approach

    DEFF Research Database (Denmark)

    Grupe, Morten; Grunnet, Morten; Bastlund, Jesper F.

    2015-01-01

    The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional character......The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional...... characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric α4β2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders...... and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the α4β2 nAChR. The potential...

  3. Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden.

    Science.gov (United States)

    Spudich, Serena; Gisslen, Magnus; Hagberg, Lars; Lee, Evelyn; Liegler, Teri; Brew, Bruce; Fuchs, Dietmar; Tambussi, Giuseppe; Cinque, Paola; Hecht, Frederick M; Price, Richard W

    2011-09-01

    Central nervous system (CNS) human immunodeficiency virus (HIV) infection and immune activation lead to brain injury and neurological impairment. Although HIV enters the nervous system soon after transmission, the magnitude of infection and immunoactivation within the CNS during primary HIV infection (PHI) has not been characterized. This cross-sectional study analyzed cerebrospinal fluid (CSF) and blood from 96 participants with PHI and compared them with samples from neuroasymptomatic participants with chronic infection and ≥ 200 or < 200 blood CD4 T cells/μL, and with samples from HIV-seronegative participants with respect to CSF and plasma HIV RNA, CSF to serum albumin ratio, and CSF white blood cell counts (WBC), neopterin levels, and concentrations of chemokines CXCL10 and CCL2. The PHI participants (median 77 days post transmission) had CSF HIV RNA, WBC, neopterin, and CXCL10 concentrations similar to the chronic infection participants but uniquely high albumin ratios. 18 participants had ≤ 100 copies/mL CSF HIV RNA, which was associated with low CSF to plasma HIV ratios and levels of CSF inflammation lower than in other PHI participants but higher than in HIV-seronegative controls. Prominent CNS infection and immune activation is evident during the first months after HIV transmission, though a proportion of PHI patients demonstrate relatively reduced CSF HIV RNA and inflammation during this early period.

  4. Utility of FDG-PETCT and magnetic resonance spectroscopy in differentiating between cerebral lymphoma and non-malignant CNS lesions in HIV-infected patients

    Energy Technology Data Exchange (ETDEWEB)

    Westwood, Thomas D., E-mail: tdwestwood@googlemail.com [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Hogan, Celia, E-mail: celiahogan@hotmail.com [Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Pennine Acute Hospitals NHS Trust (United Kingdom); Julyan, Peter J., E-mail: Peter.Julyan@christie.nhs.uk [Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Coutts, Glyn, E-mail: Glyn.Coutts@christie.nhs.uk [Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Bonington, Suzie, E-mail: suzi.bonington@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Carrington, Bernadette, E-mail: Bernadette.Carrington@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Taylor, Ben, E-mail: Ben.taylor@christie.nhs.uk [Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (United Kingdom); Khoo, Saye, E-mail: S.H.Khoo@liverpool.ac.uk [Department of Infectious Diseases and Tropical Medicine, Royal Liverpool Hospital, Liverpool (United Kingdom); Bonington, Alec, E-mail: Alec.Bonington@pat.nhs.uk [Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Pennine Acute Hospitals NHS Trust (United Kingdom)

    2013-08-15

    Background and purpose: In HIV infected patients, MRI cannot reliably differentiate between central nervous system (CNS) lymphoma and non-malignant CNS lesions, particularly cerebral toxoplasmosis (CTOX). This study prospectively investigates the utility of FDG PET-CT and magnetic resonance spectroscopy (MRS) in discriminating CNS lymphoma from non-malignant CNS lesions in HIV infected patients, and assesses the ability of FDG PET-CT to guide the use of early brain biopsy. Methods: 10 HIV patients with neurological symptoms and contrast enhancing lesions on MRI were commenced on anti-toxoplasmosis therapy before undergoing FDG PET-CT and MRS. Brain biopsies were sought in those with FDG PET-CT suggestive of CNS lymphoma, and in those with a negative FDG PET-CT scan who failed to respond to therapy. Final diagnosis was based on histology or treatment response. Results: Two patients were confirmed to have CNS lymphoma and FDG PET-CT was consistent with this diagnosis in both. Six patients had cerebral toxoplasmosis in all of whom FDG PET-CT was consistent with non-malignant disease. One patient had progressive multifocal leukoencephalopathy (PML), FDG PET-CT was equivocal. One patient had a haemorrhagic brain metastasis and FDG PET-CT wrongly suggested non-malignant disease. MRS was performed successfully in eight subjects: three results were suggestive of CNS lymphoma (one true positive, two false positive), four suggested CTOX (two false negative, two true negative), one scan was equivocal. Conclusion: FDG PET-CT correctly identified all cases of CNS lymphoma and CTOX, supporting its use in this situation. MRS was unhelpful in our cohort.

  5. Utility of FDG-PETCT and magnetic resonance spectroscopy in differentiating between cerebral lymphoma and non-malignant CNS lesions in HIV-infected patients

    International Nuclear Information System (INIS)

    Westwood, Thomas D.; Hogan, Celia; Julyan, Peter J.; Coutts, Glyn; Bonington, Suzie; Carrington, Bernadette; Taylor, Ben; Khoo, Saye; Bonington, Alec

    2013-01-01

    Background and purpose: In HIV infected patients, MRI cannot reliably differentiate between central nervous system (CNS) lymphoma and non-malignant CNS lesions, particularly cerebral toxoplasmosis (CTOX). This study prospectively investigates the utility of FDG PET-CT and magnetic resonance spectroscopy (MRS) in discriminating CNS lymphoma from non-malignant CNS lesions in HIV infected patients, and assesses the ability of FDG PET-CT to guide the use of early brain biopsy. Methods: 10 HIV patients with neurological symptoms and contrast enhancing lesions on MRI were commenced on anti-toxoplasmosis therapy before undergoing FDG PET-CT and MRS. Brain biopsies were sought in those with FDG PET-CT suggestive of CNS lymphoma, and in those with a negative FDG PET-CT scan who failed to respond to therapy. Final diagnosis was based on histology or treatment response. Results: Two patients were confirmed to have CNS lymphoma and FDG PET-CT was consistent with this diagnosis in both. Six patients had cerebral toxoplasmosis in all of whom FDG PET-CT was consistent with non-malignant disease. One patient had progressive multifocal leukoencephalopathy (PML), FDG PET-CT was equivocal. One patient had a haemorrhagic brain metastasis and FDG PET-CT wrongly suggested non-malignant disease. MRS was performed successfully in eight subjects: three results were suggestive of CNS lymphoma (one true positive, two false positive), four suggested CTOX (two false negative, two true negative), one scan was equivocal. Conclusion: FDG PET-CT correctly identified all cases of CNS lymphoma and CTOX, supporting its use in this situation. MRS was unhelpful in our cohort

  6. Effectiveness of Prescription-Based CNS Stimulants on Hospitalization in Patients With Schizophrenia

    DEFF Research Database (Denmark)

    Rohde, Christopher; Polcwiartek, Christoffer; Asztalos, Marton

    2018-01-01

    were used to investigate the effectiveness of CNS stimulants in patients with schizophrenia between 1995 and 2014; a mirror-image model with 605 individuals, using paired t tests and Wilcoxon signed rank tests, and a follow-up study with 789 individuals, using a conditional risk-set model. RESULTS: CNS...

  7. Blood-CNS Barrier Impairment in ALS Patients versus an Animal Model

    Directory of Open Access Journals (Sweden)

    Svitlana eGarbuzova-Davis

    2014-02-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a severe neurodegenerative disease with a compli-cated and poorly understood pathogenesis. Recently, alterations in the blood-Central Nervous System barrier (B-CNS-B have been recognized as a key factor possibly aggravating motor neuron damage. The majority of findings on ALS microvascular pathology have been deter-mined in mutant SOD1 rodent models, identifying barrier damage during disease develop-ment which might similarly occur in familial ALS patients carrying the SOD1 mutation. However, our knowledge of B-CNS-B competence in sporadic ALS (SALS has been limited. We recently showed structural and functional impairment in postmortem gray and white mat-ter microvessels of medulla and spinal cord tissue from SALS patients, suggesting pervasive barrier damage. Although numerous signs of barrier impairment (endothelial cell degenera-tion, capillary leakage, perivascular edema, downregulation of tight junction proteins, and microhemorrhages are indicated in both mutant SOD1 animal models of ALS and SALS pa-tients, other pathogenic barrier alterations have as yet only been identified in SALS patients. Pericyte degeneration, perivascular collagen IV expansion, and white matter capillary abnor-malities in SALS patients are significant barrier related pathologies yet to be noted in ALS SOD1 animal models. In the current review, these important differences in blood-CNS barrier damage between ALS patients and animal models, which may signify altered barrier transport mechanisms, are discussed. Understanding discrepancies in barrier condition between ALS patients and animal models may be crucial for developing effective therapies.

  8. The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    El-Galaly, Tarec Christoffer; Villa, Diego; Michaelsen, Thomas Yssing

    2017-01-01

    Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknow...

  9. T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation.

    Science.gov (United States)

    Blachère, Nathalie E; Orange, Dana E; Santomasso, Bianca D; Doerner, Jessica; Foo, Patricia K; Herre, Margaret; Fak, John; Monette, Sébastien; Gantman, Emily C; Frank, Mayu O; Darnell, Robert B

    2014-11-01

    Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form to different brain regions as a model for enzyme therapy in the CNS.

    Science.gov (United States)

    Appu, Abhilash P; Arun, Peethambaran; Krishnan, Jishnu K S; Moffett, John R; Namboodiri, Aryan M A

    2016-02-01

    The blood brain barrier (BBB) is critical for maintaining central nervous system (CNS) homeostasis by restricting entry of potentially toxic substances. However, the BBB is a major obstacle in the treatment of neurotoxicity and neurological disorders due to the restrictive nature of the barrier to many medications. Intranasal delivery of active enzymes to the brain has therapeutic potential for the treatment of numerous CNS enzyme deficiency disorders and CNS toxicity caused by chemical threat agents. The aim of this work is to provide a sensitive model system for analyzing the rapid delivery of active enzymes into various regions of the brain with therapeutic bioavailability. We tested intranasal delivery of chloramphenicol acetyltransferase (CAT), a relatively large (75kD) enzyme, in its active form into different regions of the brain. CAT was delivered intranasally to anaesthetized rats and enzyme activity was measured in different regions using a highly specific High Performance Thin Layer Chromatography (HP-TLC)-radiometry coupled assay. Active enzyme reached all examined areas of the brain within 15min (the earliest time point tested). In addition, the yield of enzyme activity in the brain was almost doubled in the brains of rats pre-treated with matrix metalloproteinase-9 (MMP-9). Intranasal administration of active enzymes in conjunction with MMP-9 to the CNS is both rapid and effective. The present results suggest that intranasal enzyme therapy is a promising method for counteracting CNS chemical threat poisoning, as well as for treating CNS enzyme deficiency disorders. Published by Elsevier B.V.

  11. Changes of CSF-protein pattern in children with acute lymphoblastic leukemia during prophylactic CNS therapy (Berlin protocol)

    International Nuclear Information System (INIS)

    Siemes, H.; Rating, D.; Siegert, M.; Hanefeld, F.; Mueller, S.; Gadner, H.; Riehm, H.

    1980-01-01

    The cerebral spinal fluid (CSF)-protein profiles of ten children with previously untreated acute lymphoblastic leukemia (ALL) were investigated by agarose gel electrophoresis. The profiles were determined at diagnosis and during the fifth to eighth week of treatment when preventive therapy for central nervous system (CNS) leukemia (skull irradiation, intrathecal methotrexate (ithMTX) was administered. The profiles were compared with those obtained from a control group of 67 children and those from 42 patients with acute aseptic meningitis. The data from the latter group demonstrated the CSF-protein pattern of partial blood-CSF barrier (B-CSF-B) breakdown. The children with ALL showed no or only minor signs of a B-CSF-B impairment at diagnosis and after four weeks of systemic treatment. However, CSF changes indicative of a lesion of the B-CSF-B increased in all children continuously during CNS prophylaxis. The protein profile at the end of combined chemotherapy and radiotherapy was very similar to that in patients with acute aseptic meningitis. These observations point to neurotoxic side effects on the CNS barrier system with the combination of cranial radiation and ithMTX. A striking finding was restricted heterogeneity of gamma-globulin, observed in the CSF of nine out of the ten children with ALL before or during treatment. The significance of this abnormality is unknown

  12. Histological characterization and quantification of cellular events following neural and fibroblast(-like) stem cell grafting in healty and demyelinated CNS tissue

    OpenAIRE

    Praet, J.; SANTERMANS, Eva; Reekmans, K.; de Vocht, N.; Le Blon, D.; Hoornaert, C.; Daans, J.; Goossens, H.; Berneman, Z.; HENS, Niel; Van der Linden, A.; Ponsaerts, P.

    2014-01-01

    Preclinical animal studies involving intracerebral (stem) cell grafting are gaining popularity in many laboratories due to the reported beneficial effects of cell grafting on various diseases or traumata of the central nervous system (CNS). In this chapter, we describe a histological workflow to characterize and quantify cellular events following neural and fibroblast(-like) stem cell grafting in healthy and demyelinated CNS tissue. First, we provide standardized protocols to isolate and cult...

  13. WAYS OF NAVIGATION SYSTEMS DEVELOPMENT WITHIN THE IMPLEMENTATION OF THE CNS/ATM CONCEPT

    Directory of Open Access Journals (Sweden)

    Igor A. Chekhov

    2017-01-01

    Full Text Available The general development principles of the civil aviation air navigation systems for the next years according to the concept of International Civil Aviation Organization (IСAO CNS/ATM are stated in the article. It was reflected in the Global air navigation plan of IСAO accepted in 2013. The author considered the structure of block modernization of aviation system directed to optimization according to four main characteristics, such as: operations at the airports; systems and data interoperable on a global scale; optimum capacity and flexible flight routes, and also effective trajectories of flight. At the same time the main attention in the plan is paid to questions of the performance based navigation (PBN, the basic theses of which lean on four main units that make the concept of PBN. The possible ways of the specified blocks implementation taking into account features of the Russian Federation airspace use are considered in this paper. On the basis of the carried-out analysis conclusions are drawn on gradual transition from the RNAV navigation specifications to the RNP specifications, on increase in accuracy of navigation by modernization of ground radio navigational aids, both on a flight route and airspace of airfield area, on need of continuing the development of inexact calling schemes, using GNSS, with the subsequent transition to schemes of exact landing approaches by means of functional additions to GLONASS – GBAS and SBAS, also on the need of opportunities research in the domestic system SBAS (SDKM for the increase in accuracy of navigation at various stages of flight. At the same time, standard instrument routes of arrival and departure (SID/STAR have to be carried out in the mode of constant climb or continuous descent.

  14. The shifting landscape of metastatic breast cancer to the CNS.

    Science.gov (United States)

    Quigley, Matthew R; Fukui, Olivia; Chew, Brandon; Bhatia, Sanjay; Karlovits, Steven

    2013-07-01

    The improved survival following the diagnosis of breast cancer has potentially altered the characteristics and course of patients presenting with CNS involvement. We therefore sought to define our current cohort of breast cancer patients with metastatic disease to the CNS in regard to modern biomarkers and clinical outcome. Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases. There were 88 women analyzed who were treated over the period of January 2003 to February 2010, average age 56.9 years. At the time of initial presentation of CNS disease, 68 % of patients had multiple brain metastases, 17 % had a solitary metastasis, and 15 % had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor-positive pathology (57.6 v. 38.2 months, p = .02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p = .004, HR = 3.1, Cox regression) and triple-negative hormonal/HER2 status (p = .02, HR = 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26 %) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33). The recently described Graded Prognostic Assessment (GPA) tumor index stratified median survival at 2.5, 5.9, 13.1, and 21.7 months, respectively, for indices of 1-4 (p = .004, log-rank), which

  15. Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

    Science.gov (United States)

    Sasayama, Daimei; Hattori, Kotaro; Ogawa, Shintaro; Yokota, Yuuki; Matsumura, Ryo; Teraishi, Toshiya; Hori, Hiroaki; Ota, Miho; Yoshida, Sumiko; Kunugi, Hiroshi

    2017-01-01

    Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. Immune and inflammatory responses in the CNS : Modulation by astrocytes

    DEFF Research Database (Denmark)

    Penkowa, Milena; aschner, michael; hidalgo, juan

    2008-01-01

    Beyond their long-recognized support functions, astrocytes are active partners of neurons in processing information, synaptic integration, and production of trophic factors, just to name a few. Both microglia and astrocytes produce and secrete a number of cytokines, modulating and integrating...... the communication between hematogenous cells and resident cells of the central nervous system (CNS). This review will address (1) the functions of astrocytes in the normal brain and (2) their role in surveying noxious stimuli within the brain, with particular emphasis on astrocytic responses to damage or disease...

  17. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P; Voskuhl, Rhonda R

    2014-02-18

    Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

  18. Diagnostic value of kinetic analysis using dynamic FDG PET in immunocompetent patients with primary CNS lymphoma

    International Nuclear Information System (INIS)

    Nishiyama, Yoshihiro; Yamamoto, Yuka; Monden, Toshihide; Sasakawa, Yasuhiro; Satoh, Katashi; Ohkawa, Motoomi; Kawai, Nobuyuki

    2007-01-01

    The purpose of this study was to investigate the accumulation of FDG in immunocompetent patients with primary central nervous system (CNS) lymphoma using qualitative and quantitative PET images and to compare baseline with follow-up PET after therapy. Twelve immunocompetent patients with CNS lymphoma were examined. Dynamic emission data were acquired for 60 min immediately following injection of FDG. In seven patients, repeated PET studies were performed after treatment. Applying a three-compartment five-parameter model, K 1 , k 2 , k 3 , k 4 , vascular fraction (V B ) and cerebral metabolic rate of glucose (CMR Glc ) were obtained. We evaluated the FDG uptake visually using qualitative and parametric images and quantitatively using parametric images. A total of 12 lesions were identified in ten patients with newly diagnosed CNS lymphoma. On visual analysis, ten lesions showed an increase on qualitative images, eight showed an increase on K 1 images, 12 showed an increase on k 3 images and ten showed an increase on CMR Glc images. On quantitative analysis, k 2 , k 3 and CMR Glc values of the lesion were significantly different from those of the normal grey matter (p 3 and CMR Glc images. The K 1 , k 2 , k 3 and CMR Glc values after treatment were significantly different from those obtained before treatment (p 3 , using dynamic FDG PET might be helpful for diagnosis of CNS lymphoma and for monitoring therapeutic assessment. (orig.)

  19. Nanotechnologies for the study of the central nervous system.

    LENUS (Irish Health Repository)

    Ajetunmobi, A

    2014-12-01

    The impact of central nervous system (CNS) disorders on the human population is significant, contributing almost €800 billion in annual European healthcare costs. These disorders not only have a disabling social impact but also a crippling economic drain on resources. Developing novel therapeutic strategies for these disorders requires a better understanding of events that underlie mechanisms of neural circuit physiology. Studying the relationship between genetic expression, synapse development and circuit physiology in CNS function is a challenging task, involving simultaneous analysis of multiple parameters and the convergence of several disciplines and technological approaches. However, current gold-standard techniques used to study the CNS have limitations that pose unique challenges to furthering our understanding of functional CNS development. The recent advancement in nanotechnologies for biomedical applications has seen the emergence of nanoscience as a key enabling technology for delivering a translational bridge between basic and clinical research. In particular, the development of neuroimaging and electrophysiology tools to identify the aetiology and progression of CNS disorders have led to new insights in our understanding of CNS physiology and the development of novel diagnostic modalities for therapeutic intervention. This review focuses on the latest applications of these nanotechnologies for investigating CNS function and the improved diagnosis of CNS disorders.

  20. [11C]NS8880, a promising PET radiotracer targeting the norepinephrine transporter

    DEFF Research Database (Denmark)

    Vase, Karina Højrup; Peters, Dan; Nielsen, Elsebeth Ø

    2014-01-01

    -azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine. METHODS: Labeling of NS8880 with [11C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [11C]methanolate...... yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [11C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [11C]NS8880. CONCLUSION: Based...... on the pre-clinical results obtained so far [11C]NS8880 displays promising properties for PET imaging of NET....

  1. Central Nervous System Vasculitis

    Science.gov (United States)

    ... of Vasculitis / Central Nervous System (CNS) Vasculitis Central Nervous System (CNS) Vasculitis Swap out your current Facebook Profile ... Facebook personal page. Replace with this image. Central nervous system (CNS) vasculitis is inflammation of blood vessel walls ...

  2. News from the editors of Fluids and Barriers of the CNS.

    Science.gov (United States)

    Drewes, Lester R; Jones, Hazel C; Keep, Richard F

    2014-01-01

    This editorial announces a new affiliation between Fluids and Barriers of the CNS (FBCNS) and the International Brain Barriers Society (IBBS) with mutual benefits to the journal and to society members. This is a natural progression from the appointment of two new Co-Editors in Chief: Professor Lester Drewes and Professor Richard Keep in 2013. FBCNS provides a unique and specialist platform for the publication of research in the expanding fields of brain barriers and brain fluid systems in both health and disease.

  3. Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

    Science.gov (United States)

    Dash, Satya; Xiao, Changting; Morgantini, Cecilia; Koulajian, Khajag; Lewis, Gary F

    2015-07-01

    In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

  4. Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Hanajiri, Ryo; Kobayashi, Takeshi; Yoshioka, Kosuke; Watanabe, Daisuke; Watakabe, Kyoko; Murata, Yutaka; Hagino, Takeshi; Seno, Yasushi; Najima, Yuho; Igarashi, Aiko; Doki, Noriko; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

    2017-03-01

    Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04). Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

  5. Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

    International Nuclear Information System (INIS)

    2015-01-01

    The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

  6. Contribution of Schwann Cells to Remyelination in a Naturally Occurring Canine Model of CNS Neuroinflammation.

    Directory of Open Access Journals (Sweden)

    Kristel Kegler

    Full Text Available Gliogenesis under pathophysiological conditions is of particular clinical relevance since it may provide evidence for regeneration promoting cells recruitable for therapeutic purposes. There is evidence that neurotrophin receptor p75 (p75NTR-expressing cells emerge in the lesioned CNS. However, the phenotype and identity of these cells, and signals triggering their in situ generation under normal conditions and certain pathological situations has remained enigmatic. In the present study, we used a spontaneous, idiopathic and inflammatory CNS condition in dogs with prominent lympho-histiocytic infiltration as a model to study the phenotype of Schwann cells and their relation to Schwann cell remyelination within the CNS. Furthermore, the phenotype of p75NTR-expressing cells within the injured CNS was compared to their counter-part in control sciatic nerve and after peripheral nerve injury. In addition, organotypic slice cultures were used to further elucidate the origin of p75NTR-positive cells. In cerebral and cerebellar white and grey matter lesions as well as in the brain stem, p75NTR-positive cells co-expressed the transcription factor Sox2, but not GAP-43, GFAP, Egr2/Krox20, periaxin and PDGFR-α. Interestingly, and contrary to the findings in control sciatic nerves, p75NTR-expressing cells only co-localized with Sox2 in degenerative neuropathy, thus suggesting that such cells might represent dedifferentiated Schwann cells both in the injured CNS and PNS. Moreover, effective Schwann cell remyelination represented by periaxin- and P0-positive mature myelinating Schwann cells, was strikingly associated with the presence of p75NTR/Sox2-expressing Schwann cells. Intriguingly, the emergence of dedifferentiated Schwann cells was not affected by astrocytes, and a macrophage-dominated inflammatory response provided an adequate environment for Schwann cells plasticity within the injured CNS. Furthermore, axonal damage was reduced in brain stem areas

  7. Primary central nervous system lymphoma in an human immunodeficiency virus-infected patient mimicking bilateral eye sign in brain seen in fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography.

    Science.gov (United States)

    Kamaleshwaran, Koramadai Karuppusany; Thirugnanam, Rajasekar; Shibu, Deepu; Kalarikal, Radhakrishnan Edathurthy; Shinto, Ajit Sugunan

    2014-04-01

    Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) has proven useful in the diagnosis, staging, and detection of metastasis and posttreatment monitoring of several malignancies in human immunodeficiency virus (HIV)-infected patients. It also has the ability to make the important distinction between malignancy and infection in the evaluation of central nervous system (CNS) lesions, leading to the initiation of the appropriate treatment and precluding the need for invasive biopsy. We report an interesting case of HIV positive 35-year-old woman presented with headache, disorientation, and decreased level of consciousness. She underwent whole body PET/CT which showed multiple lesions in the cerebrum which mimics bilateral eye in brain. A diagnosis of a primary CNS lymphoma was made and patient was started on chemotherapy.

  8. Primary central nervous system lymphoma in an human immunodeficiency virus-infected patient mimicking bilateral eye sign in brain seen in fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography

    International Nuclear Information System (INIS)

    Kamaleshwaran, Koramadai Karuppusany; Thirugnanam, Rajasekar; Shibu, Deepu; Kalarikal, Radhakrishnan Edathurthy; Shinto, Ajit Sugunan

    2014-01-01

    Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) has proven useful in the diagnosis, staging, and detection of metastasis and posttreatment monitoring of several malignancies in human immunodeficiency virus (HIV)-infected patients. It also has the ability to make the important distinction between malignancy and infection in the evaluation of central nervous system (CNS) lesions, leading to the initiation of the appropriate treatment and precluding the need for invasive biopsy. We report an interesting case of HIV positive 35-year-old woman presented with headache, disorientation, and decreased level of consciousness. She underwent whole body PET/CT which showed multiple lesions in the cerebrum which mimics bilateral eye in brain. A diagnosis of a primary CNS lymphoma was made and patient was started on chemotherapy

  9. The whole spectrum of alcohol-related changes in the CNS. Practical MR and CT imaging guidelines for daily clinical use

    International Nuclear Information System (INIS)

    Keil, V.C.; Greschus, S.; Hadizadeh, D.R.; Schild, H.H.; Schneider, C.

    2015-01-01

    Alcohol addiction is the most common drug addiction. Alcohol passes both the placenta as well as the blood-brain barrier and is in multiple ways neurotoxic. Liver diseases and other systemic alcohol-related diseases cause secondary damage to the CNS. Especially in adolescents, even a single episode of severe alcohol intoxication (''binge drinking'') may result in life-threatening neurological consequences. Alcohol-related brain and spinal cord diseases derive from multiple causes including impairment of the cellular metabolism, often aggravated by hypovitaminosis, altered neurotransmission, myelination and synaptogenesis as well as alterations in gene expression. Modern radiological diagnostics, MRI in particular, can detect the resulting alterations in the CNS with a high sensitivity. Morphological aspects often strongly correlate with clinical symptoms of the patient. It is less commonly known that many diseases considered as ''typically alcohol-related'', such as Wernicke's encephalopathy, are to a large extent not alcohol-induced. Visible CNS alterations are thus non-pathognomonic and demand careful evaluation of differential diagnoses. This review article elucidates the pathogenesis, clinical aspects and radiological image features of the most common alcohol-related CNS diseases and their differential diagnoses.

  10. Corroboration of in utero MRI using post-mortem MRI and autopsy in foetuses with CNS abnormalities

    International Nuclear Information System (INIS)

    Whitby, E.H.; Variend, S.; Rutter, S.; Paley, M.N.J.; Wilkinson, I.D.; Davies, N.P.; Sparey, C.; Griffiths, P.D.

    2004-01-01

    AIMS: To corroborate the findings of in utero magnetic resonance imaging (MRI) with autopsy and post-mortem MRI in cases of known or suspected central nervous system (CNS) abnormalities on ultrasound and to compare the diagnostic accuracy of ante-natal ultrasound and in utero MRI. METHODS: Twelve pregnant women, whose foetuses had suspected central nervous system abnormalities underwent in utero MRI. The foetuses were imaged using MRi before autopsy. The data were used to evaluate the diagnostic accuracy of in utero MRI when compared with a reference standard of autopsy and post-mortem MRI in 10 cases and post-mortem MRI alone in two cases. RESULTS: The diagnostic accuracy of antenatal ultrasound and in utero MRI in correctly characterizing brain and spine abnormalities were 42 and 100%, respectively. CONCLUSION: In utero MRI provides a useful adjuvant to antenatal ultrasound when assessing CNS abnormalities by providing more accurate anatomical information. Post-mortem MRI assists the diagnosis of macroscopic structural abnormalities

  11. Classically and alternatively activated bone marrow derived macrophages differ in cytoskeletal functions and migration towards specific CNS cell types

    Directory of Open Access Journals (Sweden)

    Dijkstra Christine D

    2011-05-01

    Full Text Available Abstract Background Macrophages play an important role in neuroinflammatory diseases such as multiple sclerosis (MS and spinal cord injury (SCI, being involved in both damage and repair. The divergent effects of macrophages might be explained by their different activation status: classically activated (CA/M1, pro-inflammatory, macrophages and alternatively activated (AA/M2, growth promoting, macrophages. Little is known about the effect of macrophages with these phenotypes in the central nervous system (CNS and how they influence pathogenesis. The aim of this study was therefore to determine the characteristics of these phenotypically different macrophages in the context of the CNS in an in vitro setting. Results Here we show that bone marrow derived CA and AA macrophages have a distinct migratory capacity towards medium conditioned by various cell types of the CNS. AA macrophages were preferentially attracted by the low weight ( Conclusion In conclusion, since AA macrophages are more motile and are attracted by NCM, they are prone to migrate towards neurons in the CNS. CA macrophages have a lower motility and a stronger adhesion to ECM. In neuroinflammatory diseases the restricted migration and motility of CA macrophages might limit lesion size due to bystander damage.

  12. Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

    Science.gov (United States)

    Swedberg, Michael D B

    2016-01-01

    Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

  13. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

    Energy Technology Data Exchange (ETDEWEB)

    Giantsoudi, Drosoula; Sethi, Roshan V. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Yeap, Beow Y. [Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts (United States); Eaton, Bree R. [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Ebb, David H. [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Caruso, Paul A.; Rapalino, Otto [Department of Radiology (O.R.) at the Massachusetts General Hospital, Boston, Massachusetts (United States); Chen, Yen-Lin E.; Adams, Judith A.; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); MacDonald, Shannon M., E-mail: smacdonald@mgh.harvard.edu [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2016-05-01

    Background: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. Methods and Materials: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. Results: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Conclusions: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

  14. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

    International Nuclear Information System (INIS)

    Giantsoudi, Drosoula; Sethi, Roshan V.; Yeap, Beow Y.; Eaton, Bree R.; Ebb, David H.; Caruso, Paul A.; Rapalino, Otto; Chen, Yen-Lin E.; Adams, Judith A.; Yock, Torunn I.; Tarbell, Nancy J.; Paganetti, Harald; MacDonald, Shannon M.

    2016-01-01

    Background: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. Methods and Materials: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. Results: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Conclusions: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

  15. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

    Science.gov (United States)

    Giantsoudi, Drosoula; Sethi, Roshan V; Yeap, Beow Y; Eaton, Bree R; Ebb, David H; Caruso, Paul A; Rapalino, Otto; Chen, Yen-Lin E; Adams, Judith A; Yock, Torunn I; Tarbell, Nancy J; Paganetti, Harald; MacDonald, Shannon M

    2016-05-01

    Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET. Published by Elsevier Inc.

  16. Are astrocytes executive cells within the central nervous system?

    Directory of Open Access Journals (Sweden)

    Roberto E. Sica

    2016-08-01

    Full Text Available ABSTRACT Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson’s disease, Alzheimer’s dementia, Huntington’s dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction. This hypothesis is supported by observations that demonstrated that the killing of neurons by non-neural cells plays a major role in the pathogenesis of those diseases, at both their onset and their progression. Furthermore, recent findings suggest that astrocytes might be involved in the pathogenesis of some psychiatric disorders as well.

  17. Computerized tomography data on CNS affection in systemic lupus erythematosus. Porazhenie tsentral'noj nervnoj sistemy pri sistemnoj krasnoj volchanke po dannym komp'yuternoj tomografii

    Energy Technology Data Exchange (ETDEWEB)

    Ivanova, M M; Bliznyuk, O I; Todua, F I; Tumanova, A A

    1989-01-01

    Computed tomography (CT) of the brain was employed in 40 patients with systemic lupus erythematosus (SLE). Clinical cerebral pathology was obvious in 30 and absent in 10 patients. By CT cerebral symptoms were divided of 4 groups. Clinical symptom complexes of CNS defects and SLE were reflected on definite CT images correlated with focal damage to the brain. CT picture of enlarged subarachnoid space, ventricles and basal cisterns can be observed in SLE patients without neurological symptoms. This indicated likely subclinical cerebral affection.

  18. Treatment options for Primary CNS Lymphoma.

    Science.gov (United States)

    Laghari, Altaf Ali; Ahmed, Syed Ijlal; Jabbar, Adnan; Shamim, Muhammad Shahzad

    2018-03-01

    Primary CNS lymphoma (PCNSL) is a rare and aggressive brain tumour that is uniformly fatal. The rarity of the disease and the poor response to treatment makes it difficult to reach a consensus with regards to treatment options. In this review, the authors have discussed different treatment modalities used in the management of PCNSL including chemotherapy, surgery and radiation, as well as the results of recent clinical trials on treatment options for PCNSL.

  19. Nuclear innovation through collaboration. 35th Annual CNS conference and 39th CNS/CNA student conference

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2015-07-01

    The Canadian Nuclear Society (CNS) held its 35th Annual Conference in Saint John, New Brunswick, Canada on May 31 to June 3, 2015, combined with the 39th Annual CNS/CNA Student Conference. With the theme of the conference, 'Nuclear Innovation through Collaboration', more than 425 delegates, exhibitors and students were in attendance. The conference commenced with two strong plenary sessions on Utility Collaborations to Improve Lifetime Performance; and, Performance Improvement Programs: Goals and Experience. The second day consisted of the panel discussions on International Developments in Used Nuclear Fuel Repository Programs, and two plenary sessions on: Enterprise Risk Management; and, Vendor Role in a Continuously Improving Industry. The third day contained a number of interesting features, including plenary sessions on Waste Management and Decommissioning; Developing Technologies and Resources, and a panel discussion on the Transportation of Used Nuclear Fuel. All three days of the conference also contained parallel sessions with over 100 technical papers presented at the main and student sessions. The technical session titles were: Refurbishment and Life Extension; Thermalhydraulics; Nuclear Materials; WMD - Radiation Monitoring; Safety and Licensing; Communication; Safety and Licensing; Instrumentation and Control; Advanced Reactor Designs; WMD - Deep Geological Repository Packaging; Reactor Physics; Chemistry and Materials; Advanced Fuel Cycles; Waste Management and Decommissioning; and, Medical Physics and Radiation Biology.

  20. Cytokine and chemokine inter-regulation in the inflamed or injured CNS

    DEFF Research Database (Denmark)

    Owens, Trevor; Babcock, Alicia A; Millward, Jason M

    2005-01-01

    the expression of chemokines in the CNS, in the absence of any other inflammatory event, but the profiles differ from those induced by axotomy. Chemokines that bind the CCR2 receptor are implicated in traffic of macrophages and T cells to the denervated hippocampus. Innate responses in the immune system...... are directed by Toll-like receptors (TLR). Our recent studies focus on specific TLR signals as upstream on-switches for glial cytokine and chemokine responses. The biological activity of chemokines is regulated by matrix metalloproteinase enzymes (MMPs) and specific members of this family are expressed...... in response to axonal lesioning. These findings strengthen the case for the sharing of signals between the immune and nervous system....

  1. Neurofeedback Control of the Human GABAergic System Using Non-invasive Brain Stimulation.

    Science.gov (United States)

    Koganemaru, Satoko; Mikami, Yusuke; Maezawa, Hitoshi; Ikeda, Satoshi; Ikoma, Katsunori; Mima, Tatsuya

    2018-06-01

    Neurofeedback has been a powerful method for self-regulating brain activities to elicit potential ability of human mind. GABA is a major inhibitory neurotransmitter in the central nervous system. Transcranial magnetic stimulation (TMS) is a tool that can evaluate the GABAergic system within the primary motor cortex (M1) using paired-pulse stimuli, short intracortical inhibition (SICI). Herein we investigated whether neurofeedback learning using SICI enabled us to control the GABAergic system within the M1 area. Forty-five healthy subjects were randomly divided into two groups: those receiving SICI neurofeedback learning or those receiving no neurofeedback (control) learning. During both learning periods, subjects made attempts to change the size of a circle, which was altered according to the degree of SICI in the SICI neurofeedback learning group, and which was altered independent of the degree of SICI in the control learning group. Results demonstrated that the SICI neurofeedback learning group showed a significant enhancement in SICI. Moreover, this group showed a significant reduction in choice reaction time compared to the control group. Our findings indicate that humans can intrinsically control the intracortical GABAergic system within M1 and can thus improve motor behaviors by SICI neurofeedback learning. SICI neurofeedback learning is a novel and promising approach to control our neural system and potentially represents a new therapy for patients with abnormal motor symptoms caused by CNS disorders. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS

    DEFF Research Database (Denmark)

    Weller, Roy O.; Sharp, Matthew M.; Christodoulides, Myron

    2018-01-01

    Meninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine...

  3. Poliovirus trafficking toward central nervous system via human poliovirus receptor-dependent and -independent pathway.

    Directory of Open Access Journals (Sweden)

    Seii eOHKA

    2012-04-01

    Full Text Available In humans, paralytic poliomyelitis results from the invasion of the central nervous system by circulating poliovirus (PV via the blood-brain barrier (BBB. After the virus enters the central nervous system (CNS, it replicates in neurons, especially in motor neurons (MNs, inducing the cell death that causes paralytic poliomyelitis. Along with this route of dissemination, neural pathway has been reported in humans, monkeys, and PV-sensitive human PV receptor (hPVR/CD155-transgenic (Tg mice. We demonstrated that a fast retrograde axonal transport process is required for PV dissemination through the sciatic nerve of hPVR-Tg mice and that intramuscularly inoculated PV causes paralysis in a hPVR-dependent manner. We also showed that hPVR-independent axonal transport of PV exists in hPVR-Tg and non-Tg mice, indicating that several different pathways for PV axonal transport exist in these mice. Circulating PV after intravenous inoculation in mice cross the BBB at a high rate in a hPVR-independent manner. Recently, we identified transferrin receptor 1 (TfR1 of mouse brain capillary endothelial cells as a binding protein to PV, implicating that TfR1 is a possible receptor for PV to permeate the BBB.

  4. Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant?

    Science.gov (United States)

    Glaser, Kirsten; Speer, Christian P

    2015-02-01

    Colonization with Ureaplasma species has been associated with adverse pregnancy outcome, and perinatal transmission has been implicated in the development of bronchopulmonary dysplasia in preterm neonates. Little is known about Ureaplasma-mediated infection and inflammation of the CNS in neonates. Controversy remains concerning its incidence and implication in the pathogenesis of neonatal brain injury. In vivo and in vitro data are limited. Despite improving care options for extremely immature preterm infants, relevant complications remain. Systematic knowledge of ureaplasmal infection may be of great benefit. This review aims to summarize pathogenic mechanisms, clinical data and diagnostic pitfalls. Studies in preterm and term neonates are critically discussed with regard to their limitations. Clinical questions concerning therapy or prophylaxis are posed. We conclude that ureaplasmas may be true pathogens, especially in preterm neonates, and may cause CNS inflammation in a complex interplay of host susceptibility, serovar pathogenicity and gestational age-dependent CNS vulnerability.

  5. Utility of MRI versus tumor markers for post-treatment surveillance of marker-positive CNS germ cell tumors.

    Science.gov (United States)

    Cheung, Victoria; Segal, Devorah; Gardner, Sharon L; Zagzag, David; Wisoff, Jeffrey H; Allen, Jeffrey C; Karajannis, Matthias A

    2016-09-01

    Patients with marker-positive central nervous system (CNS) germ cell tumors are typically monitored for tumor recurrence with both tumor markers (AFP and b-hCG) and MRI. We hypothesize that the recurrence of these tumors will always be accompanied by an elevation in tumor markers, and that surveillance MRI may not be necessary. We retrospectively identified 28 patients with CNS germ cell tumors treated at our institution that presented with an elevated serum or cerebrospinal fluid (CSF) tumor marker at the time of diagnosis. We then identified those who had a tumor recurrence after having been in remission and whether each recurrence was detected via MRI changes, elevated tumor markers, or both. Four patients suffered a tumor recurrence. Only one patient had simultaneously elevated tumor markers and MRI evidence of recurrence. Two patients had evidence of recurrence on MRI without corresponding elevations in serum or CSF tumor markers. One patient had abnormal tumor markers with no evidence of recurrence on MRI until 6 months later. We conclude that in patients with marker-positive CNS germ cell tumors who achieve complete remission, continued surveillance imaging in addition to measurement of tumor markers is indicated to detect recurrences.

  6. Development of allosteric modulators of GPCRs for treatment of CNS disorders.

    Science.gov (United States)

    Nickols, Hilary Highfield; Conn, P Jeffrey

    2014-01-01

    The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. © 2013.

  7. Use of multiplex PCR based molecular diagnostics in diagnosis of suspected CNS infections in tertiary care setting-A retrospective study.

    Science.gov (United States)

    Javali, Mahendra; Acharya, Purushottam; Mehta, Aneesh; John, Aju Abraham; Mahale, Rohan; Srinivasa, R

    2017-10-01

    CNS infections like meningitis and encephalitis pose enormous healthcare challenges due to mortality, sequelae and socioeconomic burden. In tertiary setting, clinical, microbiological, cytological and radiological investigations are not distinctive enough for diagnosing microbial etiology. Molecular diagnostics is filling this gap. We evaluated the clinical impact of a commercially available multiplex molecular diagnostic system - SES for diagnosing suspected CNS infections. This study was conducted in our tertiary level Neurology ICU. 110 patients admitted during Nov-2010 to April-2014 were included. CSF samples of patients clinically suspected of having CNS infections were subjected to routine investigation in our laboratory and SES test at XCyton Diagnostics. We studied the impact of SES in diagnosis of CNS infections and its efficacy in helping therapeutic management. SES showed detection rate of 42.18% and clinical specificity of 100%. It had 10 times higher detection rate than conventional tests. Streptococcus pneumoniae and Mycobacterium tuberculosis were two top bacterial pathogens. VZV was most detected viral pathogen. SES results elicited changes in therapy in both positive and negative cases. We observed superior patient outcomes as measured by GCS scale. 75% and 82.14% of the patients positive and negative on SES respectively, recovered fully. Detecting causative organism and ruling out infectious etiology remain the most critical aspect for management and prognosis of patients with suspected CNS infections. In this study, we observed higher detection rate of pathogens, target specific escalation and evidence based de-escalation of antimicrobials using SES. Institution of appropriate therapy helped reduce unnecessary use of antimicrobials. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS.

    Directory of Open Access Journals (Sweden)

    Soo Jin Park

    Full Text Available Central nervous system (CNS inflammatory demyelinating diseases (IDDs are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS, neuromyelitis optica spectrum disorder (NMOSD, and idiopathic transverse myelitis (ITM. Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls. Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

  9. In vivo evaluation in rats of [18F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

    International Nuclear Information System (INIS)

    Waterhouse, Rikki N.; Chang, Raymond C.; Zhao, Jun; Carambot, Patty E.

    2006-01-01

    Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K D =0.5±0.2 nM, log P=2.9) sigma-1 receptor radiotracer [ 18 F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [ 18 F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [ 18 F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [ 18 F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([ 18 F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [ 18 F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([ 18 F]SFE) (K D =5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [ 18 F]SFE was synthesized (n=4) as previously described in good yield (54±6% EOB), high specific activity (2.1±0.6 Ci/μmol EOS) and radiochemical purity (98±1%) and evaluated in awake adult male rats. Results: Similar to [ 18 F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [ 18 F]SFE were highest in occipital cortex (1.86±0.06 %ID/g) and frontal cortex (1.76±0.38 %ID/g), and lowest in the hippocampus (1.01±0.02%ID/g). Unlike [ 18 F]FPS, [ 18 F]SFE cleared from the brain with ∼40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [ 18 F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [ 18 F]SFE in discrete brain regions. Conclusions: We conclude that [ 18 F]SFE exhibits excellent characteristics in vivo and may provide

  10. Imaging aspects of neurologic emergencies in children treated for non-CNS malignancies

    International Nuclear Information System (INIS)

    Kaste, S.C.; Langston, J.; Rodriguez-Galindo, C.; Furman, W.L.; Thompson, S.J.

    2000-01-01

    There is a paucity of radiologic literature addressing neurologic emergencies in children receiving therapy for non-CNS primary malignancies. In the acute setting, many of these children present to local community hospitals. This pictorial is from a single institutional experience describing the spectrum of neurologic emergencies seen in children with non-CNS cancers. We hope to familiarize pediatric radiologists with these entities in order to expedite diagnosis, facilitate treatment, and minimize morbity and mortality that may be associated with these complications. (orig.)

  11. Transplantation of autologous bone marrow stromal cells (BMSC for CNS disorders – Strategy and tactics for clinical application

    Directory of Open Access Journals (Sweden)

    Satoshi Kuroda

    2010-01-01

    Full Text Available Background – There is increasing evidence that the transplanted bone marrow stromal cells (BMSC significantly promote functional recovery after central nervous system (CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, brain contusion and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with neurological disorders. In this paper, therefore, we discuss what we should clarify to establish cell transplantation therapy in clinical situation and describe our recent works for this purpose.Methods and Results – The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. Using optical imaging and MRI techniques, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. Functional imaging such as PET scan may have the potential to assess the beneficial effects of BMSC transplantation. The BMSC can be expanded using the animal protein-free culture medium, which would maintain their potential of proliferation, migration, and neural differentiation.Conclusion – It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future

  12. Metallothionein-1+2 protect the CNS after a focal brain injury

    DEFF Research Database (Denmark)

    Giralt, Mercedes; Penkowa, Milena; Lago, Natalia

    2002-01-01

    We have evaluated the physiological relevance of metallothionein-1+2 (MT-1+2) in the CNS following damage caused by a focal cryolesion onto the cortex. In comparison to normal mice, transgenic mice overexpressing the MT-1 isoform (TgMTI* mice) showed a significant decrease of the number...... dramatically reduced the cryolesion-induced oxidative stress and neuronal apoptosis. Remarkably, these effects were also obtained by the intraperitoneal administration of MT-2 to both normal and MT-1+2 knock-out mice. These results fully support the notion that MT-1+2 are essential in the CNS for coping...

  13. Cancers of the Brain and CNS: Global Patterns and Trends in Incidence.

    Science.gov (United States)

    Mortazavi, S M J; Mortazavi, S A R; Paknahad, M

    2018-03-01

    Miranda-Filho et al. in their recently published paper entitled "Cancers of the brain and CNS: global patterns and trends in incidence" provided a global status report of the geographic and temporal variations in the incidence of brain and CNS cancers in different countries across continents worldwide. While the authors confirm the role of genetic risk factors and ionizing radiation exposures, they claimed that no firm conclusion could be drawn about the role of exposure to non-ionizing radiation. The paper authored by Miranda-Filho et al. not only addresses a challenging issue, it can be considered as a good contribution in the field of brain and CNS cancers. However, our correspondence addresses a basic shortcoming of this paper about the role of electromagnetic fields and cancers and provides evidence showing that exposure to radiofrequency electromagnetic fields (RF-EMFs), at least at high levels and long durations, can increases the risk of cancer.

  14. BOBATH THERAPY IN CORRECTION OF PSYCHOMOTOR DEVELOPMENT OF CHILDREN WITH ORGANIC INJURIES CNS

    OpenAIRE

    Bukhovets, B. O.; Romanchuk, A. P.

    2014-01-01

    The article represents therapy of Bobath such as one of the most effective author method which use in correction psychomotor development of children with disorders of musculoskeletal system. Bobath method is not new in the correction of movement disorders since last century and still supplementing and improving. In this work highlight topic of the effective use Bobath therapy in correction of psychomotor development in children age 3 – 6 years with organic involvement CNS. the experiment w...

  15. Antiviral type I and type III interferon responses in the central nervous system.

    Science.gov (United States)

    Sorgeloos, Frédéric; Kreit, Marguerite; Hermant, Pascale; Lardinois, Cécile; Michiels, Thomas

    2013-03-15

    The central nervous system (CNS) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB) from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs) are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i) preventing neuroinvasion and infection of CNS cells; ii) the identity of IFN-producing cells in the CNS; iii) the antiviral activity of ISGs; and iv) the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  16. Antiviral Type I and Type III Interferon Responses in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Thomas Michiels

    2013-03-01

    Full Text Available The central nervous system (CNS harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. This organ is partly protected by the blood-brain barrier (BBB from toxic substances and pathogens carried in the bloodstream. Yet, neurotropic viruses can reach the CNS either by crossing the BBB after viremia, or by exploiting motile infected cells as Trojan horses, or by using axonal transport. Type I and type III interferons (IFNs are cytokines that are critical to control early steps of viral infections. Deficiencies in the IFN pathway have been associated with fatal viral encephalitis both in humans and mice. Therefore, the IFN system provides an essential protection of the CNS against viral infections. Yet, basal activity of the IFN system appears to be low within the CNS, likely owing to the toxicity of IFN to this organ. Moreover, after viral infection, neurons and oligodendrocytes were reported to be relatively poor IFN producers and appear to keep some susceptibility to neurotropic viruses, even in the presence of IFN. This review addresses some trends and recent developments concerning the role of type I and type III IFNs in: i preventing neuroinvasion and infection of CNS cells; ii the identity of IFN-producing cells in the CNS; iii the antiviral activity of ISGs; and iv the activity of viral proteins of neurotropic viruses that target the IFN pathway.

  17. Safety analysis report for packaging (onsite) for limited type Bmaterial in the CNS 14-215H cask

    International Nuclear Information System (INIS)

    Flanagan, B.D.

    1997-01-01

    The purpose of this Safety Analysis Report for Packaging is to provide the analyses and evaluations necessary to demonstrate that the CNS 14-215H cask provided by Chem-Nuclear Systems Inc. can safety transport greater than Type A quantities of radioactive material on the Hanford Site. The CNS 14-215H cask was chosen for its loading abilities, availability, and because it has a Certificate of Compliance (CoC) issued by the U.S. Nuclear Regulatory Commission (NRC) for transporting low specific activity in quantities greater than Type A material in commerce. Although the CDC does not cover greater than Type A material not meeting LSA requirements, it does allow for an established level of protection in determining the safety of transporting Type B material on the Hanford Site

  18. CD11c-expressing cells affect Treg behavior in the meninges during CNS infection1

    Science.gov (United States)

    O’Brien, Carleigh A.; Overall, Christopher; Konradt, Christoph; O’Hara Hall, Aisling C.; Hayes, Nikolas W.; Wagage, Sagie; John, Beena; Christian, David A.; Hunter, Christopher A.; Harris, Tajie H.

    2017-01-01

    Treg cells play an important role in the CNS during multiple infections as well as autoimmune inflammation, but the behavior of this cell type in the CNS has not been explored. In mice, infection with Toxoplasma gondii leads to a Th1-polarized parasite-specific effector T cell response in the brain. Similarly, the Treg cells in the CNS during T. gondii infection are Th1-polarized, exemplified by T-bet, CXCR3, and IFN-γ expression. Unlike effector CD4+ T cells, an MHC Class II tetramer reagent specific for T. gondii did not recognize Treg cells isolated from the CNS. Likewise, TCR sequencing revealed minimal overlap in TCR sequence between effector and regulatory T cells in the CNS. Whereas effector T cells are found in the brain parenchyma where parasites are present, Treg cells were restricted to the meninges and perivascular spaces. The use of intravital imaging revealed that activated CD4+ T cells within the meninges were highly migratory, while Treg cells moved more slowly and were found in close association with CD11c+ cells. To test whether the behavior of Tregs in the meninges is influenced by interactions with CD11c+ cells, mice were treated with anti-LFA-1 antibodies to reduce the number of CD11c+ cells in this space. The anti-LFA-1 treatment led to fewer contacts between Tregs and the remaining CD11c+ cells and increased the speed of Treg cell migration. These data suggest that Treg cells are anatomically restricted within the CNS and the interaction with CD11c+ populations regulates their local behavior during T. gondii infection. PMID:28389591

  19. Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor.

    Science.gov (United States)

    Hinson, Shannon R; Clift, Ian C; Luo, Ningling; Kryzer, Thomas J; Lennon, Vanda A

    2017-05-23

    Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

  20. Human herpesvirus infections of the central nervous system: laboratory diagnosis based on DNA detection by nested PCR in plasma and cerebrospinal fluid samples.

    Science.gov (United States)

    Rimério, Carla Aparecida Tavares; De Oliveira, Renato Souza; de Almeida Bonatelli, Murilo Queiroz; Nucci, Anamarli; Costa, Sandra Cecília Botelho; Bonon, Sandra Helena Alves

    2015-04-01

    Infections of the central nervous systems (CNS) present a diagnostic problem for which an accurate laboratory diagnosis is essential. Invasive practices, such as cerebral biopsy, have been replaced by obtaining a polymerase chain reaction (PCR) diagnosis using cerebral spinal fluid (CSF) as a reference method. Tests on DNA extracted from plasma are noninvasive, thus avoiding all of the collateral effects and patient risks associated with CSF collection. This study aimed to determine whether plasma can replace CSF in nested PCR analysis for the detection of CNS human herpesvirus (HHV) diseases by analysing the proportion of patients whose CSF nested PCR results were positive for CNS HHV who also had the same organism identified by plasma nested PCR. In this study, CSF DNA was used as the "gold standard," and nested PCR was performed on both types of samples. Fifty-two patients with symptoms of nervous system infection were submitted to CSF and blood collection. For the eight HHV, one positive DNA result-in plasma and/or CSF nested PCR-was considered an active HHV infection, whereas the occurrence of two or more HHVs in the same sample was considered a coinfection. HHV infections were positively detected in 27/52 (51.9%) of the CSF and in 32/52 (61.5%) of the plasma, difference not significant, thus nested PCR can be performed on plasma instead of CSF. In conclusion, this findings suggest that plasma as a useful material for the diagnosis of cases where there is any difficulty to perform a CSF puncture. © 2015 Wiley Periodicals, Inc.

  1. Spontaneous nervous system concussion in dogs: A description of ...

    African Journals Online (AJOL)

    In human medicine, central nervous system (CNS) concussion is defined as a transient neurological dysfunction following a traumatic event, without evidence of structural abnormalities of the affected region on advanced diagnostic imaging. Depending on the anatomical region involved, three forms of concussive ...

  2. A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

    Science.gov (United States)

    Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

    2017-11-02

    The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

  3. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology

    Directory of Open Access Journals (Sweden)

    Jessica M Hogestyn

    2018-01-01

    Full Text Available Human herpesviruses (HVs have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system (CNS. The ability of HVs to enter a state of latency, a defining characteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease (NDD pathology by highlighting two prominent members of the HV family, herpes simplex virus 1 (HSV-1 and human herpesvirus 6 (HHV-6. We (i introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then (ii review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer's disease (AD and multiple sclerosis (MS, respectively. We then (iii highlight and discuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we (iv discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

  4. Isolation of mineralizing Nestin+ Nkx6.1+ vascular muscular cells from the adult human spinal cord

    Directory of Open Access Journals (Sweden)

    Guillon Hélène

    2011-10-01

    Full Text Available Abstract Background The adult central nervous system (CNS contains different populations of immature cells that could possibly be used to repair brain and spinal cord lesions. The diversity and the properties of these cells in the human adult CNS remain to be fully explored. We previously isolated Nestin+ Sox2+ neural multipotential cells from the adult human spinal cord using the neurosphere method (i.e. non adherent conditions and defined medium. Results Here we report the isolation and long term propagation of another population of Nestin+ cells from this tissue using adherent culture conditions and serum. QPCR and immunofluorescence indicated that these cells had mesenchymal features as evidenced by the expression of Snai2 and Twist1 and lack of expression of neural markers such as Sox2, Olig2 or GFAP. Indeed, these cells expressed markers typical of smooth muscle vascular cells such as Calponin, Caldesmone and Acta2 (Smooth muscle actin. These cells could not differentiate into chondrocytes, adipocytes, neuronal and glial cells, however they readily mineralized when placed in osteogenic conditions. Further characterization allowed us to identify the Nkx6.1 transcription factor as a marker for these cells. Nkx6.1 was expressed in vivo by CNS vascular muscular cells located in the parenchyma and the meninges. Conclusion Smooth muscle cells expressing Nestin and Nkx6.1 is the main cell population derived from culturing human spinal cord cells in adherent conditions with serum. Mineralization of these cells in vitro could represent a valuable model for studying calcifications of CNS vessels which are observed in pathological situations or as part of the normal aging. In addition, long term propagation of these cells will allow the study of their interaction with other CNS cells and their implication in scar formation during spinal cord injury.

  5. Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

    Science.gov (United States)

    Brown, Melissa A; Weinberg, Rebecca B

    2018-01-01

    Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4 + and CD8 + T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

  6. Drug Elucidation: Invertebrate Genetics Sheds New Light on the Molecular Targets of CNS Drugs

    Directory of Open Access Journals (Sweden)

    Donard S. Dwyer

    2014-07-01

    Full Text Available Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

  7. Evaluation of intrafraction patient movement for CNS and head and neck IMRT

    International Nuclear Information System (INIS)

    Kim, Siyong; Akpati, Hilary C.; Kielbasa, Jerrold E.; Li, Jonathan G.; Liu, Chihray; Amdur, Robert J.; Palta, Jatinder R.

    2004-01-01

    Intrafraction patient motion is much more likely in intensity-modulated radiation therapy (IMRT) than in conventional radiotherapy primarily due to longer beam delivery times in IMRT treatment. In this study, we evaluated the uncertainty of intrafraction patient displacement in CNS and head and neck IMRT patients. Immobilization is performed in three steps: (1) the patient is immobilized with thermoplastic facemask, (2) the patient displacement is monitored using a commercial stereotactic infrared IR camera (ExacTrac, BrainLab) during treatment, and (3) repositioning is carried out as needed. The displacement data were recorded during beam-on time for the entire treatment duration for 5 patients using the camera system. We used the concept of cumulative time versus patient position uncertainty, referred to as an uncertainty time histogram (UTH), to analyze the data. UTH is a plot of the accumulated time during which a patient stays within the corresponding movement uncertainty. The University of Florida immobilization procedure showed an effective immobilization capability for CNS and head and neck IMRT patients by keeping the patient displacement less than 1.5 mm for 95% of treatment time (1.43 mm for 1, and 1.02 mm for 1, and less than 1.0 mm for 3 patients). The maximum displacement was 2.0 mm

  8. Humanized mice: models for evaluating NeuroHIV and cure strategies.

    Science.gov (United States)

    Honeycutt, Jenna B; Garcia, J Victor

    2018-04-01

    While the human immunodeficiency virus (HIV) epidemic was initially characterized by a high prevalence of severe and widespread neurological pathologies, the development of better treatments to suppress viremia over years and even decades has mitigated many of the severe neurological pathologies previously observed. Despite effective treatment, mild neurocognitive impairment and premature cognitive aging are observed in HIV-infected individuals, suggesting a changing but ongoing role of HIV infection in the central nervous system (CNS). Although current therapies are effective in suppressing viremia, they are not curative and patients must remain on life-long treatment or risk recrudescence of virus. Important for the development and evaluation of a cure for HIV will be animal models that recapitulate critical aspects of infection in vivo. In the following, we seek to summarize some of the recent developments in humanized mouse models and their usefulness in modeling HIV infection of the CNS and HIV cure strategies.

  9. [Human transmissible subacute spongiform encephalopathy].

    Science.gov (United States)

    Dormont, D

    1994-05-01

    Human transmissible spongiform encephalopathies (TSE) are rare chronic subacute degenerative diseases of the central nervous system (CNS) which include Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). CJD can be either inherited or sporadic. All these diseases are always fatal. Neuropathological features are mainly constituted of neuronal vacuolisation, neuronal death, gliosis with hyperastrocytosis; plaques might be evidenced in kuru and GSS. Neither inflammatory syndrome nor demyelination is detectable. No virus like structure could be identified reproducibly. Human TSE are transmissible to non human primates and rodents. Iatrogenic CJD have been described after tissue grafting (cornea, dura mater), neurosurgery, electrophysiology investigation, and treatment with pituitary derived gonadotrophins and growth hormone. Molecular biochemistry of the CNS investigation revealed that a host encoded protein, the prion protein (PrP), accumulates proportionally to the infectious titer: this abnormality is the only detectable hallmark in TSE. Infectious fractions contain no detectable specific nucleic acid, and are mainly constituted of PrP under an isoform which resists to proteinase K digestion (PrP-res). The PrP gene (PRNP) is located on chromosome 20 in humans. Several mutations of this gene have been described in all inherited TSE (CJD, GSS, and IFF). No treatment is available today. Agents inducing TSE (TSA) are not known: several authors claim that TSA are only constituted of PrP-res; others support the hypothesis of a conventional agent with a specific genetic information.

  10. Nasal-to-CNS drug delivery: where are we now and where are we heading? An industrial perspective.

    Science.gov (United States)

    Landis, Margaret S; Boyden, Tracey; Pegg, Simon

    2012-02-01

    Delivery of drug therapeutics across the blood-brain barrier is a challenging task for pharmaceutical scientists. Nasal-to-CNS drug delivery has shown promising results in preclinical efficacy models and investigatory human clinical trials. The further development of this technology with respect to the establishment of valid, predictable preclinical species models, translatable pharmacokinetic-pharmacodynamic relationships and definition of toxicology impact will help attract additional pharmaceutical investment in this drug-delivery approach. Further discoveries in nasal nanotechnology, targeted delivery devices and diagnostic olfactory imaging will serve to fuel the advancements in this area of drug delivery.

  11. Interaction of Plant Extracts with Central Nervous System Receptors

    Directory of Open Access Journals (Sweden)

    Kenneth Lundstrom

    2017-02-01

    Full Text Available Background: Plant extracts have been used in traditional medicine for the treatment of various maladies including neurological diseases. Several central nervous system receptors have been demonstrated to interact with plant extracts and components affecting the pharmacology and thereby potentially playing a role in human disease and treatment. For instance, extracts from Hypericum perforatum (St. John’s wort targeted several CNS receptors. Similarly, extracts from Piper nigrum, Stephania cambodica, and Styphnolobium japonicum exerted inhibition of agonist-induced activity of the human neurokinin-1 receptor. Methods: Different methods have been established for receptor binding and functional assays based on radioactive and fluorescence-labeled ligands in cell lines and primary cell cultures. Behavioral studies of the effect of plant extracts have been conducted in rodents. Plant extracts have further been subjected to mood and cognition studies in humans. Results: Mechanisms of action at molecular and cellular levels have been elucidated for medicinal plants in support of standardization of herbal products and identification of active extract compounds. In several studies, plant extracts demonstrated affinity to a number of CNS receptors in parallel indicating the complexity of this interaction. In vivo studies showed modifications of CNS receptor affinity and behavioral responses in animal models after treatment with medicinal herbs. Certain plant extracts demonstrated neuroprotection and enhanced cognitive performance, respectively, when evaluated in humans. Noteworthy, the penetration of plant extracts and their protective effect on the blood-brain-barrier are discussed. Conclusion: The affinity of plant extracts and their isolated compounds for CNS receptors indicates an important role for medicinal plants in the treatment of neurological disorders. Moreover, studies in animal and human models have confirmed a scientific basis for the

  12. Neurolymphomatosis: An International Primary CNS Lymphoma Collaborative Group report

    NARCIS (Netherlands)

    S. Grisariu (Sigal); B. Avni (Batia); T.T. Batchelor (Tracy); M.J. van den Bent (Martin); F. Bokstein (Felix); D. Schiff (David); O. Kuittinen (Outi); M.C. Chamberlain (Marc C.); P. Roth (Patrick); A. Nemets (Anatoly); E. Shalom (Edna); D. Ben-Yehuda (Dina); T. Siegal (Tali)

    2010-01-01

    textabstractNeurolymphomatosis (NL) is a rare clinical entity. The International Primary CNS Lymphoma Collaborative Group retrospectively analyzed 50 patients assembled from 12 centers in 5 countries over a 16-year period. NL was related to non-Hodgkin lymphoma in 90% and to acute leukemia in 10%.

  13. Central nervous system lipocalin-type prostaglandin D2-synthase is correlated with orexigenic neuropeptides, visceral adiposity and markers of the hypothalamic-pituitary-adrenal axis in obese humans.

    Science.gov (United States)

    Elias, E; Benrick, A; Behre, C J; Ekman, R; Zetterberg, H; Stenlöf, K; Wallenius, V

    2011-06-01

    Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ = 0.695, P fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

  14. Liraglutide Reduces CNS Activation in Response to Visual Food Cues Only After Short-term Treatment in Patients With Type 2 Diabetes.

    Science.gov (United States)

    Ten Kulve, Jennifer S; Veltman, Dick J; van Bloemendaal, Liselotte; Barkhof, Frederik; Drent, Madeleine L; Diamant, Michaela; IJzerman, Richard G

    2016-02-01

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with reduced appetite and body weight. We investigated whether these effects could be mediated by the central nervous system (CNS). We performed a randomized crossover study in obese patients with type 2 diabetes (n = 20, mean age 59.3 ± 4.1 years, mean BMI 32 ± 4.7 kg/m(2)), consisting of two periods of 12-week treatment with either liraglutide 1.8 mg or insulin glargine. Using functional MRI, we determined the effects of treatment on CNS responses to viewing food pictures in the fasted condition and 30 min after meal intake. After 12 weeks, the decrease in HbA1c was larger with liraglutide versus insulin glargine (Δ-0.7% vs. -0.2%, P food pictures in insula and putamen (P ≤ 0.02). In addition, liraglutide enhanced the satiating effect of meal intake on responses in putamen and amygdala (P ≤ 0.05). Differences between liraglutide and insulin glargine were not observed after 12 weeks. Compared with insulin, liraglutide decreased CNS activation significantly only after short-term treatment, suggesting that these effects of GLP-1RA on the CNS may contribute to the induction of weight loss, but not necessarily to its maintenance, in view of the absence of an effect of liraglutide on CNS activation in response to food pictures after longer-term treatment. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  15. A map of taste neuron projections in the Drosophila CNS

    Indian Academy of Sciences (India)

    2014-07-08

    Jul 8, 2014 ... information that they represent. The extensive ... physiology and behaviour in the wild type and in these mutants .... taste information is processed in the CNS. 2. ..... gene affecting the specificity of the chemosensory neurons of.

  16. Malignant lymphoma in central nervous system (CNS). Report of a case with characteristic CT finding and amnesia

    Energy Technology Data Exchange (ETDEWEB)

    Fujiyoshi, Kenji; Fukuyama, Hidenao; Akiguchi, Ichiro; Kameyama, Masakuni [Kyoto Univ. (Japan). Faculty of Medicine; Nishimura, Toshio

    1984-07-01

    A 71-year-old male was admitted to Kohka Public Hospital on January 4, 1980, because of frequent vomiting and recent memory loss. Two weeks before admission upper G-I series showed no abnormalities. Physical and neurological examinations revealed no abnormalities except for slightly apathetic appearance and recent memory loss. Mild pleocytosis and marked increase of protein in CSF were observed. CT scan on January 17 showed high density areas in both medial sides of temporal lobes with remarkable contrast enhancement. His memory and, consciousness disturbances gradually aggravated, accompanied by abnormal density spreading around the ventricle walls like ventriculitis. He was transfered to Kyoto University Hospital on March 17, and malignant lymphoma was diagnosed on the basis of CSF cytology. Radiation and chemotherapy alleviated the CNS involvement and he regained normal mental function. On June 16, he developed pneumonia followed by status epilepticus. Autopsy findings revealed no lymphoid cell infiltration, but fibrous tissues in both hippocampal gyri and lymphomatous cells in the liver, which could not be suspected on clinical examinations. Apparent malignant lymphoma cells were not found in lymph nodes. This case indicated peculiar evolution of malignant lymphoma from liver to CNS or vice versa. We could not decide which organ was primary. CT findings of this case was very interesting; they resembled ventriculitis, which simulate tumors such as medulloblastoma or ependymoma spreading under ependymal lining.

  17. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases

    DEFF Research Database (Denmark)

    Kerrn-Jespersen, B M; Lindelof, M; Illes, Zsolt

    2014-01-01

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appeara...

  18. [Dementia in Patients with Central Nervous System Mycosis].

    Science.gov (United States)

    Morita, Akihiko; Ishihara, Masaki; Konno, Michiko

    2016-04-01

    Central nervous system (CNS) mycosis is a potentially life-threatening but treatable neurological emergency. CNS mycoses progress slowly and are sometimes difficult to distinguish from dementia. Though most patients with CNS mycosis have an underlying disease, such as human immunodeficiency virus (HIV) infection, cancer, diabetes mellitus, and/or use of immunosuppressants, cryptococcosis can occur in non-immunosuppressed persons. One of the major difficulties in accurate diagnosis is to detect the pathogen in patients' cerebrospinal fluid (CSF) cultures. Thus, the clinical diagnosis is often made by combining circumstantial evidence, including mononuclear cell-dominant pleocytosis with low glucose and protein elevation in the CSF, as well as positive results from an antigen-based assay and a (1-3)-beta-D-glucan assay using plasma and/or CSF. Polymerase chain reaction (PCR)-based diagnostics, which are not performed as routine examinations and are mostly performed as part of academic research in Japan, are sensitive tools for the early diagnosis of CNS mycosis. Mognetic resonance imaging (MRI) is useful to assess the complications of fungal meningitis, such as abscess, infarction, and hydrocephalus. Clinicians should realize the advantages and disadvantages of these diagnostic tools. Early and accurate diagnosis, including identification of the particular fungal species, enables optimal antifungal treatment that produces good outcomes in patients with CNS mycosis.

  19. MR findings of central nervous system involvement in acquired immunodeficiency syndrome patient : a report of two cases

    International Nuclear Information System (INIS)

    Hong, Hye Suk; Kim, Dong Ik; Lee, Byeong Hee; Jeong, Sun Yang

    1996-01-01

    Central nervous system (CNS) manifestations in acquired immunodeficiency syndrome (AIDS) patients are an early and common feature. The spectrum of AIDS-related CNS diseases are encephalitis caused by the human immunodeficiency virus(HIV) itself, opportunistic infection, infarct and malignancy. We experienced two cases of CNS involvement in AIDS and they were serologically diagnosed as HIV encephalitis and CNS toxoplasmosis, respectively. In the case of the HIV encephalitis patient, brain MRI showed a non-enhancing lesion with high signal intensity on T2WI and low signal on T1WI and there was no mass effect on the right frontal lobe, periventricular white matter, splenium of the corpus callosum or bilateral basal ganglia. In the other case of CNS toxoplasmosis, MR showed multiple nodular and rim enhanced mass lesions in the right basal ganglia, thalamus and periventricular white matter, which were of low signal intensity on T1WI and of high intensity on T2WI. We thus report the related MRI findings

  20. CNS imaging findings associated with Parry-Romberg syndrome and en coup de sabre: correlation to dermatologic and neurologic abnormalities.

    Science.gov (United States)

    Doolittle, Derrick A; Lehman, Vance T; Schwartz, Kara M; Wong-Kisiel, Lily C; Lehman, Julia S; Tollefson, Megha M

    2015-01-01

    Parry-Romberg syndrome (PRS) and en coup de sabre (ECS) are variants of morphea. Although numerous findings on central nervous system (CNS) imaging of PRS and ECS have been reported, the spectrum and frequency of CNS imaging findings and relation to cutaneous and neurologic abnormalities have not been fully characterized. We retrospectively reviewed patients younger than 50 years at our institution over a 16-year interval who had clinical diagnosis of PRS and ECS by a skin or facial subspecialist. Two neuroradiologists evaluated available imaging and characterized CNS imaging findings. Eighty-eight patients with PRS or ECS were identified (62 women [70.4 %]; mean age 28.8 years). Of the 43 patients with CNS imaging, 19 (44 %) had abnormal findings. The only finding in 1 of these 19 patients was lateral ventricle asymmetry; of the other 18, findings were bilateral in 11 (61 %), ipsilateral to the side of facial involvement in 6 (33 %), and contralateral in 1 (6 %). Sixteen patients had serial imaging examinations over an average of 632 days; 13 (81 %) had stable imaging findings, and 3 (19 %) had change over time. Of six patients with progressive cutaneous findings, five (83 %) had stable imaging findings over time. Among the 23 patients with clinical neurologic abnormality and imaging, 12 (52 %) had abnormal imaging findings. All seven patients with seizures (100 %) had abnormal imaging studies. In PRS and ECS, imaging findings often are bilateral and often do not progress, regardless of cutaneous disease activity. Findings are inconsistently associated with clinical abnormalities.

  1. Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice

    Energy Technology Data Exchange (ETDEWEB)

    Farfán-García, E.D.; Pérez-Rodríguez, M. [Academias de Fisiología Humana, Bioquímica y Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 Ciudad de México (Mexico); Espinosa-García, C. [Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana (UAM), 09310 Ciudad de México (Mexico); Castillo-Mendieta, N.T.; Maldonado-Castro, M.; Querejeta, E.; Trujillo-Ferrara, J.G. [Academias de Fisiología Humana, Bioquímica y Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, 11340 Ciudad de México (Mexico); and others

    2016-09-15

    The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥ 200 mg/kg, and involving granular cell damage at doses of 400 mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system. - Highlights: • Intraperitoneal 3-thienylboronic acid (3TB) induces tremor in CD1 or C57BL6 mice. • Injury on CNS as well as motor disruption is dose-dependent. • Damage is greater in basal ganglia than in cerebellum or motor cortex. • The DMSO as vehicle plays a key role in the induced effect. • Motor disruption seems to involve basal ganglia and cerebellum damage.

  2. Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice

    International Nuclear Information System (INIS)

    Farfán-García, E.D.; Pérez-Rodríguez, M.; Espinosa-García, C.; Castillo-Mendieta, N.T.; Maldonado-Castro, M.; Querejeta, E.; Trujillo-Ferrara, J.G.

    2016-01-01

    The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥ 200 mg/kg, and involving granular cell damage at doses of 400 mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system. - Highlights: • Intraperitoneal 3-thienylboronic acid (3TB) induces tremor in CD1 or C57BL6 mice. • Injury on CNS as well as motor disruption is dose-dependent. • Damage is greater in basal ganglia than in cerebellum or motor cortex. • The DMSO as vehicle plays a key role in the induced effect. • Motor disruption seems to involve basal ganglia and cerebellum damage.

  3. Human herpesvirus 6A induces apoptosis of primary human fetal astrocytes via both caspase-dependent and -independent pathways

    Directory of Open Access Journals (Sweden)

    Gu Bin

    2011-12-01

    Full Text Available Abstract Background Human herpesvirus 6 (HHV-6 is a T-lymphtropic and neurotropic virus that can infect various types of cells. Sequential studies reported that apoptosis of glia and neurons induced by HHV-6 might act a potential trigger for some central nervous system (CNS diseases. HHV-6 is involved in the pathogenesis of encephalitis, multiple sclerosis (MS and fatigue syndrome. However, the mechanisms responsible for the apoptosis of infected CNS cells induced by HHV-6 are poorly understood. In this study, we investigated the cell death processes of primary human fetal astrocytes (PHFAs during productive HHV-6A infection and the underlying mechanisms. Results HHV-6A can cause productive infection in primary human fetal astrocytes. Annexin V-PI staining and electron microscopic analysis indicated that HHV-6A was an inducer of apoptosis. The cell death was associated with activation of caspase-3 and cleavage of poly (ADP-ribose polymerase (PARP, which is known to be an important substrate for activated caspase-3. Caspase-8 and -9 were also significantly activated in HHV-6A-infected cells. Moreover, HHV-6A infection led to Bax up-regulation and Bcl-2 down-regulation. HHV-6A infection increased the release of Smac/Diablo, AIF and cytochrome c from mitochondria to cytosol, which induced apoptosis via the caspase-dependent and -independent pathways. In addition, we also found that anti-apoptotic factors such as IAPs and NF-κB decreased in HHV-6A infected PHFAs. Conclusion This is the first demonstration of caspase-dependent and -independent apoptosis in HHV-6A-infected glial cells. These findings would be helpful in understanding the mechanisms of CNS diseases caused by HHV-6.

  4. Transplantation dose alters the dynamics of human neural stem cell engraftment, proliferation and migration after spinal cord injury

    Directory of Open Access Journals (Sweden)

    Katja M. Piltti

    2015-09-01

    Full Text Available The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell (hNSC engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell proliferation at 2 weeks post-transplant (WPT and dose-normalized engraftment at 16 WPT. Critically, mice receiving the highest cell dose exhibited an engraftment plateau, in which the total number of engrafted human cells never exceeded the initial dose. These data suggest that donor cell expansion was inversely regulated by target niche parameters and/or transplantation density. Investigation of the response of donor cells to the host microenvironment should be a key variable in defining target cell dose in pre-clinical models of CNS disease and injury.

  5. Clinicopathologic features of adult T-cell leukemias/lymphomas at a North American tertiary care medical center: infrequent involvement of the central nervous system.

    Science.gov (United States)

    Hsi, Andy C; Kreisel, Friederike H; Frater, John L; Nguyen, TuDung T

    2014-02-01

    Human T-cell lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma (ATLL). Published series of ATLLs seen at a United States medical institution are rare. We present the features of 4 ATLLs diagnosed at our North American tertiary care medical center from 1990 to 2012. Despite the absence of a history of origin from an endemic region, all our ATLLs demonstrated evidence of human T-cell lymphotropic virus type 1 infection. Central nervous system (CNS) involvement by ATLL was uncommon in our series, and represented only 1.6% (1/64) of all CNS B-cell or T-cell lymphomas diagnosed over a 20+ year period at our institution. Review of the medical literature reveals that the majority of CNS-involved ATLLs present with the lymphoma or acute subtype, and complete remission is difficult to achieve in these cases. CNS involvement frequently occurs with a systemic disease, which carries an aggressive clinical course with poor prognosis. In addition, CNS involvement by ATLL can be the initial presentation or seen with relapsed disease, can be the only site or be associated with other tissue sites of involvement, and may manifest with variable clinical signs/symptoms. Our retrospective study reveals that ATLLs are rare mature T-cell lymphomas in a native North American population, but the clinical and histopathologic features of ATLLs from this nonendemic region are similar to those seen from other endemic regions. Early recognition of these rare ATLLs involving uncommon sites, such as the CNS, will help optimize treatment for these infrequent mature T-cell lymphomas.

  6. Biophysics Representation of the Two-Hit Model of Alzheimer's Disease for the Exploration of Late CNS Risks from Space Radiation

    Science.gov (United States)

    Cucinotta, Francis A.; Ponomarev, Artem

    2009-01-01

    A concern for long-term space travel outside the Earth s magnetic field is the late effects to the central nervous system (CNS) from galactic cosmic ray (GCR) or solar particle events (SPE). Human epidemiology data is severely limited for making CNS risk estimates and it is not clear such effects occur following low LET exposures. We are developing systems biology models based on biological information on specific diseases, and experimental data for proton and heavy ion radiation. A two-hit model of Alzheimer s disease (AD) has been proposed by Zhu et al.(1), which is the framework of our model. Of importance is that over 50% of the US population over the age of 75-y have mild to severe forms of AD. Therefore we recommend that risk assessment for a potential AD risk from space radiation should focus on the projection of an earlier age of onset of AD and the prevention of this possible acceleration through countermeasures. In the two-hit model, oxidative stress and aberrant cell cycle-related abnormalities leading to amyloid-beta plaques and neurofibrillary tangles are necessary and invariant steps in AD. We have formulated a stochastic cell kinetics model of the two-hit AD model. In our model a population of neuronal cells is allowed to undergo renewal through neurogenesis and is susceptible to oxidative stress or cell cycle abnormalities with age-specific accumulation of damage. Baseline rates are fitted to AD population data for specific ages, gender, and for persons with an apolipoprotein 4 allele. We then explore how low LET or heavy ions may increase either of the two-hits or neurogenesis either through persistent oxidative stress, direct mutation, or through changes to the micro-environment, and suggest possible ways to develop accurate quantitative estimates of these processes for predicting AD risks following long-term space travel.

  7. Comparative analysis of acid sphingomyelinase distribution in the CNS of rats and mice following intracerebroventricular delivery.

    Directory of Open Access Journals (Sweden)

    Christopher M Treleaven

    Full Text Available Niemann-Pick A (NPA disease is a lysosomal storage disorder (LSD caused by a deficiency in acid sphingomyelinase (ASM activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO mice could be partially alleviated by intracerebroventricular (ICV infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.

  8. Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

    International Nuclear Information System (INIS)

    Colleoni, Silvia; Galli, Cesare; Giannelli, Serena G.; Armentero, Marie-Therese; Blandini, Fabio; Broccoli, Vania; Lazzari, Giovanna

    2010-01-01

    In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

  9. Long-term culture and differentiation of CNS precursors derived from anterior human neural rosettes following exposure to ventralizing factors

    Energy Technology Data Exchange (ETDEWEB)

    Colleoni, Silvia, E-mail: silviacolleoni@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Galli, Cesare [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy); Dipartimento Clinico Veterinario, Universita di Bologna, Via Tolara di Sopra 50, 40064 Ozzano Emilia (Italy); Giannelli, Serena G. [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Armentero, Marie-Therese; Blandini, Fabio [Laboratory of Functional Neurochemistry, Interdepartmental Research Center for Parkinson' s Disease, Neurological Institute C. Mondino, Via Mondino 2, 27100 Pavia (Italy); Broccoli, Vania, E-mail: broccoli.vania@hsr.it [Stem Cells and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan (Italy); Lazzari, Giovanna, E-mail: giovannalazzari@avantea.it [Laboratorio di Tecnologie della Riproduzione, Avantea, Via Porcellasco 7/f, 26100 Cremona (Italy)

    2010-04-15

    In this study we demonstrated that neural rosettes derived from human ES cells can give rise either to neural crest precursors, following expansion in presence of bFGF and EGF, or to dopaminergic precursors after exposure to ventralizing factors Shh and FGF8. Both regionalised precursors are capable of extensive proliferation and differentiation towards the corresponding terminally differentiated cell types. In particular, peripheral neurons, cartilage, bone, smooth muscle cells and also pigmented cells were obtained from neural crest precursors while tyrosine hydroxylase and Nurr1 positive dopaminergic neurons were derived from FGF8 and Shh primed rosette cells. Gene expression and immunocytochemistry analyses confirmed the expression of dorsal and neural crest genes such as Sox10, Slug, p75, FoxD3, Pax7 in neural precursors from bFGF-EGF exposed rosettes. By contrast, priming of rosettes with FGF8 and Shh induced the expression of dopaminergic markers Engrailed1, Pax2, Pitx3, floor plate marker FoxA2 and radial glia markers Blbp and Glast, the latter in agreement with the origin of dopaminergic precursors from floor plate radial glia. Moreover, in vivo transplant of proliferating Shh/FGF8 primed precursors in parkinsonian rats demonstrated engraftment and terminal dopaminergic differentiation. In conclusion, we demonstrated the derivation of long-term self-renewing precursors of selected regional identity as potential cell reservoirs for cell therapy applications, such as CNS degenerative diseases, or for the development of toxicological tests.

  10. Sex-specific effects of dehydroepiandrosterone (DHEA) on glucose metabolism in the CNS.

    Science.gov (United States)

    Vieira-Marques, Claudia; Arbo, Bruno Dutra; Cozer, Aline Gonçalves; Hoefel, Ana Lúcia; Cecconello, Ana Lúcia; Zanini, Priscila; Niches, Gabriela; Kucharski, Luiz Carlos; Ribeiro, Maria Flávia M

    2017-07-01

    DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases. Copyright © 2016. Published by Elsevier Ltd.

  11. Commercial viability of CNS drugs: balancing the risk/reward profile.

    Science.gov (United States)

    Johnson, Ginger S

    2014-01-01

    CNS has historically been a formidable therapeutic area in which to innovate owing to biological (e.g., complex neurobiology, difficulty reaching the target), as well as clinical (e.g., subjective clinical endpoints, high placebo response, lack of biomarkers) challenges. In the current market where many of the larger diseases are dominated by a generic standard of care, commercial challenges now make the triple threat of scientific-clinical-commercial risk too much for many players to tackle. However, opportunities do exist for smaller biotech companies to concentrate on narrowly focused patient populations associated with high unmet need for which risk can be tightly defined. In CNS, there are two major areas to balance the risk/reward profile and create commercially viable opportunities: To realize value, all companies (start-ups and big players) must define, measure and quantify clear and meaningful value to all stakeholders: physicians, patients, caregivers and payers. © 2013.

  12. Evidence of end-effector based gait machines in gait rehabilitation after CNS lesion.

    Science.gov (United States)

    Hesse, S; Schattat, N; Mehrholz, J; Werner, C

    2013-01-01

    A task-specific repetitive approach in gait rehabilitation after CNS lesion is well accepted nowadays. To ease the therapists' and patients' physical effort, the past two decades have seen the introduction of gait machines to intensify the amount of gait practice. Two principles have emerged, an exoskeleton- and an endeffector-based approach. Both systems share the harness and the body weight support. With the end-effector-based devices, the patients' feet are positioned on two foot plates, whose movements simulate stance and swing phase. This article provides an overview on the end-effector based machine's effectiveness regarding the restoration of gait. For the electromechanical gait trainer GT I, a meta analysis identified nine controlled trials (RCT) in stroke subjects (n = 568) and were analyzed to detect differences between end-effector-based locomotion + physiotherapy and physiotherapy alone. Patients practising with the machine effected in a superior gait ability (210 out of 319 patients, 65.8% vs. 96 out of 249 patients, 38.6%, respectively, Z = 2.29, p = 0.020), due to a larger training intensity. Only single RCTs have been reported for other devices and etiologies. The introduction of end-effector based gait machines has opened a new succesful chapter in gait rehabilitation after CNS lesion.

  13. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs

    Directory of Open Access Journals (Sweden)

    Vik-Mo Audun O

    2006-10-01

    Full Text Available Abstract Background The etiology of schizophrenia is unknown, but neurodevelopmental disturbances, myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder. Cholesterol is an essential component of myelin and has proved important for synapse formation. Recently, we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein (SREBP transcription factors. We here compare the action of chlorpromazine, haloperidol, clozapine, olanzapine, risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression (ACAT2, HMGCR, HMGCS1, FDPS, SC5DL, DHCR7, LDLR, FASN and SCD1 in four CNS-relevant human cell lines. Results There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes, with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations. Glial-like cells (GaMg glioma and CCF-STTG1 astrocytoma cell lines displayed more pronounced drug-induced SREBP activation compared to the response in HCN2 human cortical neurons and SH-SY5Y neuroblastoma cells, indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells. Conclusion Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells. We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs.

  14. Metallothionein Expression and Roles During Neuropathology in the CNS

    DEFF Research Database (Denmark)

    Penkowa, Milena

    2006-01-01

    , their receptors and neurotrophins (TGFb, TGFb-Receptor, bFGF, bFGF-Receptor, VEGF, NT-3, NT-4/5, NGF); angiogenesis; and growth cone formation. Hence, MT-I+II enhance CNS tissue repair as seen clearly after the cryogenic injury, after which MT-I+II promote substitution of the necrotic lesion cavity with a glial...

  15. In vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Waterhouse, Rikki N. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States) and Department of Radiology, Columbia University, New York, NY 10032 (United States) and Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)]. E-mail: rnw7@columbia.edu; Chang, Raymond C. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Zhao, Jun [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States); Carambot, Patty E. [Department of Psychiatry, Columbia University, New York, NY 10032 (United States); Neurobiology and Imaging Program, Department of Biological Psychiatry, New York State Psychiatric Institute, New York, NY 10032 (United States)

    2006-02-15

    Introduction: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K {sub D}=0.5{+-}0.2 nM, log P=2.9) sigma-1 receptor radiotracer [{sup 18}F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [{sup 18}F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [{sup 18}F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [{sup 18}F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([{sup 18}F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [{sup 18}F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([{sup 18}F]SFE) (K {sub D}=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. Methods: [{sup 18}F]SFE was synthesized (n=4) as previously described in good yield (54{+-}6% EOB), high specific activity (2.1{+-}0.6 Ci/{mu}mol EOS) and radiochemical purity (98{+-}1%) and evaluated in awake adult male rats. Results: Similar to [{sup 18}F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [{sup 18}F]SFE were highest in occipital cortex (1.86{+-}0.06 %ID/g) and frontal cortex (1.76{+-}0.38 %ID/g), and lowest in the hippocampus (1.01{+-}0.02%ID/g). Unlike [{sup 18}F]FPS, [{sup 18}F]SFE cleared from the brain with {approx}40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [{sup 18}F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [{sup 18}F]SFE in discrete brain regions. Conclusions

  16. Primary CNS Nonamyloidogenic Light Chain Deposition Disease: Case Report and Brief Review.

    Science.gov (United States)

    Mercado, Juan Jose; Markert, James M; Meador, William; Chapman, Philip; Perry, Arie; Hackney, James R

    2017-12-01

    The true incidence of light chain deposition disease (LCDD) restricted to the central nervous system (CNS) is unknown. To our knowledge only 7 cases of LCDD restricted to the brain have been previously reported. We herein describe an unusual example. A 44-year-old man presented with a history of ischemic retinopathy in 2004 and left lower extremity hypoesthesia in 2007 that progressed gradually to left-sided weakness and numbness in the 2 years prior to his hospitalization in 2015. A stereotactic brain biopsy was performed, displaying nonspecific hyaline deposits of amorphous "amyloid-like" material involving deep brain white matter and vessels. These were Congo red negative and were accompanied by a sparse lymphoplasmacytic infiltrate. Plasma cells demonstrated kappa light chain class restriction by chromogenic in situ hybridization (CISH). There was patchy reactivity with kappa immunohistochemistry in the amorphous deposits. A diagnosis of light chain deposition disease was made. Subsequent systemic myeloma and lymphoma workups were negative. Previously reported cases have included men and women, spanning the ages of 19 and 72 years, often presenting with hemiparesis, hypoesthesia, or seizures. Deposits have been reported in the cerebrum and cerebellum. T2/FLAIR (fluid attenuation inversion recovery) changes are usual, but lesions may or may not produce contrast enhancement. The light chain deposition may be of kappa or lambda class. Most lesions have been accompanied by local lymphoid and/or plasma cell infiltrates exhibiting light chain restriction of the same class as the deposits. In summary, LCDD limited to the CNS is a rare lesion consisting of deposition of amyloid-like, but Congo red-negative monotypic light chain usually produced by local lymphoplasmacytic infiltrates.

  17. Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system

    Directory of Open Access Journals (Sweden)

    Virginie eBonnamain

    2012-04-01

    Full Text Available Neural transplantation is a promising therapeutic strategy for neurodegenerative diseases and other affections of the central nervous system (CNS like Parkinson and Huntington diseases, multiple sclerosis or stroke. If cell replacement therapy already went through clinical trials for some of these diseases using fetal human neuroblasts, several important limitations led to the search for alternative cell sources that would be more suitable for intracerebral transplantation. Taking into account logistical and ethical issues linked to the use of tissue derived from human fetuses, and the immunologically special status of the CNS allowing the occurrence of deleterious immune reactions, Neural Stem/Progenitor Cells (NSPCs appear as an interesting cell source candidate. In addition to their ability for replacing cell populations lost during the pathological events, NSPCs also display surprising therapeutic effects of neuroprotection and immunomodulation. A better knowledge of the mechanisms involved in these specific characteristics will hopefully lead in the future to a successful use of NSPCs in regenerative medicine for CNS affections.

  18. Diversity and antimicrobial susceptibility profiling of staphylococci isolated from bovine mastitis cases and close human contacts.

    Science.gov (United States)

    Schmidt, T; Kock, M M; Ehlers, M M

    2015-09-01

    The objectives of this study were to examine the diversity of Staphylococcus spp. recovered from bovine intramammary infections and humans working in close contact with the animals and to evaluate the susceptibility of the staphylococcal isolates to different antimicrobials. A total of 3,387 milk samples and 79 human nasal swabs were collected from 13 sampling sites in the KwaZulu-Natal province of South Africa. In total, 146 Staph. aureus isolates and 102 coagulase-negative staphylococci (CNS) were recovered from clinical and subclinical milk samples. Staphylococcusaureus was isolated from 12 (15.2%) of the human nasal swabs and 95 representative CNS were recovered for further characterization. The CNS were identified using multiplex-PCR assays, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and tuf gene sequencing. Seven Staphylococcus spp. were identified among the CNS of bovine origin, with Staph.chromogenes (78.4%) predominating. The predominant CNS species recovered from the human nasal swabs was Staph.epidermidis (80%) followed by Staph.chromogenes (6.3%). The antimicrobial susceptibility of all staphylococcal isolates was evaluated using disk diffusion and was supplemented by screening for specific antimicrobial resistance genes. Ninety-eight (67.1%) Staph.aureus isolates of bovine origin were pansusceptible; 39 (26.7%) isolates were resistant to a single class, and 7 (4.8%) isolates were resistant to 2 classes of antimicrobials. Two Staph. aureus (1.4%) isolates were multidrug-resistant. Resistance to penicillin was common, with 28.8% of the bovine and 75% of the human Staph. aureus isolates exhibiting resistance. A similar observation was made with the CNS, where 37.3% of the bovine and 89.5% of the human isolates were resistant to penicillin. Multidrug-resistance was common among the human CNS, with 39% of the isolates exhibiting resistance to 3 or more classes of antimicrobials. The antimicrobial

  19. The Effect of the Uncariae Ramulus et Uncus on the Regeneration Following CNS Injury

    Directory of Open Access Journals (Sweden)

    Lee Jin-Goo

    2009-03-01

    Full Text Available Objective : Following central nervous system(CNS injury, inhibitory influences at the site of axonal damage occur. Glial cells become reactive and form a glial scar, gliosis. Also myelin debris such as MAG inhibits axonal regeneration. Astrocyte-rich gliosis relates with up-regulation of GFAP and CD81, and eventually becomes physical and mechanical barrier to axonal regeneration. MAG is one of several endogenous axon regeneration inhibitors that limit recovery from CNS injury and disease. It was reported that molecules that block such inhibitors enhanced axon regeneration and functional recovery. Recently it was reported that treatment with anti-CD81 antibodies enhanced functional recovery in the rat with spinal cord injury. So in this current study, the author investigated the effect of the water extract of Uncariae Ramulus et Uncus on the regulation of CD81, GFAP and MAG that increase when gliosis occurs. Methods : MTT assay was performed to examine cell viability, and cell-based ELISA, western blot and PCR were used to detect the expression of CD81, GFAP and MAG. Then also immunohistochemistry was performed to confirm in vivo. Results : Water extract of Uncariae Ramulus et Uncus showed relatively high cell viability at the concentration of 0.05%, 0.1% and 0.5%. The expression of CD81, GFAP and MAG in astrocytes was decreased after the administration of Uncariae Ramulus et Uncus water extract. These results was confirmed in the brain sections following cortical stab injury by immunohistochemistry. Conclusion : The authors observed that Uncariae Ramulus et Uncus significantly down-regulates the expression of CD81, GFAP and MAG. These results suggest that Uncariae Ramulus et Uncus can be a candidate to regenerate CNS injury.

  20. CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

    Science.gov (United States)

    Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

    2007-01-01

    Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

  1. Growth of Malignant Non-CNS Tumors Alters Brain Metabolome

    Science.gov (United States)

    Kovalchuk, Anna; Nersisyan, Lilit; Mandal, Rupasri; Wishart, David; Mancini, Maria; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga

    2018-01-01

    Cancer survivors experience numerous treatment side effects that negatively affect their quality of life. Cognitive side effects are especially insidious, as they affect memory, cognition, and learning. Neurocognitive deficits occur prior to cancer treatment, arising even before cancer diagnosis, and we refer to them as “tumor brain.” Metabolomics is a new area of research that focuses on metabolome profiles and provides important mechanistic insights into various human diseases, including cancer, neurodegenerative diseases, and aging. Many neurological diseases and conditions affect metabolic processes in the brain. However, the tumor brain metabolome has never been analyzed. In our study we used direct flow injection/mass spectrometry (DI-MS) analysis to establish the effects of the growth of lung cancer, pancreatic cancer, and sarcoma on the brain metabolome of TumorGraft™ mice. We found that the growth of malignant non-CNS tumors impacted metabolic processes in the brain, affecting protein biosynthesis, and amino acid and sphingolipid metabolism. The observed metabolic changes were similar to those reported for neurodegenerative diseases and brain aging, and may have potential mechanistic value for future analysis of the tumor brain phenomenon. PMID:29515623

  2. Treatment of HIV in the CNS: effects of antiretroviral therapy and the promise of non-antiretroviral therapeutics.

    Science.gov (United States)

    Peluso, Michael J; Spudich, Serena

    2014-09-01

    The growing recognition of the burden of neurologic disease associated with HIV infection in the last decade has led to renewed efforts to characterize the pathophysiology of the virus within the central nervous system (CNS). The concept of the AIDS-dementia complex is now better understood as a spectrum of HIV-associated neurocognitive disorders (HAND), which range from asymptomatic disease to severe impairment. Recent work has shown that even optimally treated patients can experience not only persistent HAND, but also the development of new neurologic abnormalities despite viral suppression. This has thrown into question what the impact of antiretroviral therapy has been on the incidence and prevalence of neurocognitive dysfunction. In this context, the last few years have seen a concentrated effort to identify the effects that antiretroviral therapy has on the neurologic manifestations of HIV and to develop therapeutic modalities that might specifically alter the trajectory of HIV within the CNS.

  3. Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

    DEFF Research Database (Denmark)

    Zeka, Bleranda; Hastermann, Maria; Hochmeister, Sonja

    2015-01-01

    In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since...

  4. Interactions of the histamine and hypocretin systems in CNS disorders.

    Science.gov (United States)

    Shan, Ling; Dauvilliers, Yves; Siegel, Jerome M

    2015-07-01

    Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy-associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system.

  5. The Emerging Roles for Telomerase in the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Meng-Ying Liu

    2018-05-01

    Full Text Available Telomerase, a specialized ribonucleoprotein enzyme complex, maintains telomere length at the 3′ end of chromosomes, and functions importantly in stem cells, cancer and aging. Telomerase exists in neural stem cells (NSCs and neural progenitor cells (NPCs, at a high level in the developing and adult brains of humans and rodents. Increasing studies have demonstrated that telomerase in NSCs/NPCs plays important roles in cell proliferation, neuronal differentiation, neuronal survival and neuritogenesis. In addition, recent works have shown that telomerase reverse transcriptase (TERT can protect newborn neurons from apoptosis and excitotoxicity. However, to date, the link between telomerase and diseases in the central nervous system (CNS is not well reviewed. Here, we analyze the evidence and summarize the important roles of telomerase in the CNS. Understanding the roles of telomerase in the nervous system is not only important to gain further insight into the process of the neural cell life cycle but would also provide novel therapeutic applications in CNS diseases such as neurodegenerative condition, mood disorders, aging and other ailments.

  6. Vascular, glial, and lymphatic immune gateways of the central nervous system

    NARCIS (Netherlands)

    Engelhardt, Britta; Carare, Roxana O.; Bechmann, Ingo; Fluegel, Alexander; Laman, Jon D.; Weller, Roy O.

    Immune privilege of the central nervous system (CNS) has been ascribed to the presence of a blood-brain barrier and the lack of lymphatic vessels within the CNS parenchyma. However, immune reactions occur within the CNS and it is clear that the CNS has a unique relationship with the immune system.

  7. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics.

    Science.gov (United States)

    Louveau, Antoine; Plog, Benjamin A; Antila, Salli; Alitalo, Kari; Nedergaard, Maiken; Kipnis, Jonathan

    2017-09-01

    Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems.

  8. Central nervous system prophylaxis in diffuse large B-cell lymphoma.

    Science.gov (United States)

    Zahid, Mohammad Faizan; Khan, Nadia; Hashmi, Shahrukh K; Kizilbash, Sani Haider; Barta, Stefan K

    2016-08-01

    Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Widespread transduction of astrocytes and neurons in the mouse central nervous system after systemic delivery of a self-complementary AAV-PHP.B vector.

    Science.gov (United States)

    Rincon, Melvin Y; de Vin, Filip; Duqué, Sandra I; Fripont, Shelly; Castaldo, Stephanie A; Bouhuijzen-Wenger, Jessica; Holt, Matthew G

    2018-04-01

    Until recently, adeno-associated virus 9 (AAV9) was considered the AAV serotype most effective in crossing the blood-brain barrier (BBB) and transducing cells of the central nervous system (CNS), following systemic injection. However, a newly engineered capsid, AAV-PHP.B, is reported to cross the BBB at even higher efficiency. We investigated how much we could boost CNS transgene expression by using AAV-PHP.B carrying a self-complementary (sc) genome. To allow comparison, 6 weeks old C57BL/6 mice received intravenous injections of scAAV2/9-GFP or scAAV2/PHP.B-GFP at equivalent doses. Three weeks postinjection, transgene expression was assessed in brain and spinal cord. We consistently observed more widespread CNS transduction and higher levels of transgene expression when using the scAAV2/PHP.B-GFP vector. In particular, we observed an unprecedented level of astrocyte transduction in the cortex, when using a ubiquitous CBA promoter. In comparison, neuronal transduction was much lower than previously reported. However, strong neuronal expression (including spinal motor neurons) was observed when the human synapsin promoter was used. These findings constitute the first reported use of an AAV-PHP.B capsid, encapsulating a scAAV genome, for gene transfer in adult mice. Our results underscore the potential of this AAV construct as a platform for safer and more efficacious gene therapy vectors for the CNS.

  10. Statistical challenges in a regulatory review of cardiovascular and CNS clinical trials.

    Science.gov (United States)

    Hung, H M James; Wang, Sue-Jane; Yang, Peiling; Jin, Kun; Lawrence, John; Kordzakhia, George; Massie, Tristan

    2016-01-01

    There are several challenging statistical problems identified in the regulatory review of large cardiovascular (CV) clinical outcome trials and central nervous system (CNS) trials. The problems can be common or distinct due to disease characteristics and the differences in trial design elements such as endpoints, trial duration, and trial size. In schizophrenia trials, heavy missing data is a big problem. In Alzheimer trials, the endpoints for assessing symptoms and the endpoints for assessing disease progression are essentially the same; it is difficult to construct a good trial design to evaluate a test drug for its ability to slow the disease progression. In CV trials, reliance on a composite endpoint with low event rate makes the trial size so large that it is infeasible to study multiple doses necessary to find the right dose for study patients. These are just a few typical problems. In the past decade, adaptive designs were increasingly used in these disease areas and some challenges occur with respect to that use. Based on our review experiences, group sequential designs (GSDs) have borne many successful stories in CV trials and are also increasingly used for developing treatments targeting CNS diseases. There is also a growing trend of using more advanced unblinded adaptive designs for producing efficacy evidence. Many statistical challenges with these kinds of adaptive designs have been identified through our experiences with the review of regulatory applications and are shared in this article.

  11. A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells.

    Science.gov (United States)

    Shroff, Geeta

    2018-01-01

    Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.

  12. CARR-CNS with crescent-shape moderator cell and sub-cooling helium jacket surrounding cell

    International Nuclear Information System (INIS)

    Yu, Qingfeng; Feng, Quanke; Kawai, Takeshi; Shen, Feng; Yuan, Luzheng

    2005-01-01

    The new type of the moderator cell was developed for the Cold Neutron Source (CNS) of the China Advanced Research Reactor (CARR) which is now constructing at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the sub-cooling helium jacket is adopted. A crescent-shape would help to increase the volume of the moderator cell for corresponding it to the 4 cold neutron guide tubes, even if liquid hydrogen not liquid deuterium were used as a cold moderator. The sub-cooling helium jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the inner shell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down firstly into the sub-cooling helium jacket and then flows up to the condenser. Therefore, the theory of the self-regulation for the thermo-siphon type of the CNS is also applicable

  13. CARR-CNS with crescent-shape moderator cell and sub-cooling helium jacket around cell

    International Nuclear Information System (INIS)

    Yu, Qingfeng; Feng, Quanke; Kawai, Takeshi; Cheng, Liang; Shen, Feng; Yuan, Luzheng

    2005-01-01

    The new type of the moderator cell was developed for the Cold Neutron Source (CNS) of the China Advanced Research Reactor (CARR) which is now constructing at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the sub-cooling helium jacket is adopted. A crescent-shape would help to increase the volume of the moderator cell for corresponding it to the 4 cold neutron guide tubes, even if liquid hydrogen not liquid deuterium were used as a cold moderator. The sub-cooling helium jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the inner shell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down firstly into the sub-cooling helium jacket and then flows up to the condenser. Therefore, the theory of the self-regulation for the thermo-siphon type of the CNS is also applicable

  14. Influence of mercury and CNS irradation upon the dynamics of the skeletal musculature

    International Nuclear Information System (INIS)

    Johnson, R.M.

    1981-01-01

    The existence of different mechanisms of central nervous system damage from CNS irradiation and chronic mercurial poisoning implies a possible synergism of effect from the two insults. In order to determine the level of hazard from this combined insult, a two way treatment was given to twelve groups of female Holtzman rats. The mortality data yield the surprising result that CNS irradiation has the effect of marginally extending the life of mercury poisoned rats. The work output versus time revealed that rats reach their maximum work output of about 2.5 millihorsepower at about one year of age. Rats with zero and low mercury give about the same maximal work output patterns. Those who have been ingesting 25 ppM are feeble, putting out around 10 microhorsepower. The only apparent effect of radiation is a drop in work output at about one year of age for the 5000 R rats. The effect of experimental insult upon the growth and weight patterns of the rats differed with their mercury level, while the effect of their irradiation status was of less importance. It is to be noted that over all the characteristics observed, the combined insults of radiation and mercurialism produced not synergism of effect. In fact, there are indications in several places that the effects of the insults are actually antagonistic

  15. An in vitro clonogenic assay to assess radiation damage in rat CNS glial progenitor cells

    International Nuclear Information System (INIS)

    Maazen, R.W.M. van der; Verhagen, I.; Kogel, A.J. van der

    1990-01-01

    Normal glial progenitor cells can be isolated from the rat central nervous system (CNS) and cultured in vitro on a monolayer of type-1 astrocytes. These monolayers are able to support and stimulate explanted glial progenitor cells to proliferate. Employing these in vitro interactions of specific glial cell types, an in vivo-in vitro clonogenic assay has been developed. This method offers the possibility to study the intrinsic radiosensitivity, repair and regeneration of glial progenitor cells after in vitro or in vivo irradiation. (author)

  16. Discrimination of different brain metastases and primary CNS lymphomas using morphologic criteria and diffusion tensor imaging

    Energy Technology Data Exchange (ETDEWEB)

    Bette, S.; Wiestler, B.; Huber, T.; Boeckh-Behrens, T.; Zimmer, C.; Kirschke, J. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neuroradiology; Delbridge, C. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neuropathology; Meyer, B.; Gempt, J. [Technical University Munich, Klinikum rechts der Isar (Germany). Dept. of Neurosurgery

    2016-12-15

    Brain metastases are a common complication of cancer and occur in about 15-40% of patients with malignancies. The aim of this retrospective study was to differentiate between metastases from different primary tumors/CNS lymphyomas using morphologic criteria, fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Morphologic criteria such as hemorrhage, cysts, pattern of contrast enhancement and location were reported in 200 consecutive patients with brain metastases/primary CNS lymphomas. FA and ADC values were measured in regions of interest (ROIs) placed in the contrast-enhancing tumor part, the necrosis and the non-enhancing peritumoral region (NEPTR). Differences between histopathological subtypes of metastases were analyzed using non-parametric tests, decision trees and hierarchical clustering analysis. Significant differences were found in morphologic criteria such as hemorrhage or pattern of contrast enhancement. In diffusion measurements, significant differences between the different tumor entities were only found in ADC analyzed in the contrast-enhancing tumor part. Among single tumor entities, primary CNS lymphomas showed significantly lower median ADC values in the contrast-enhancing tumor part (ADC{sub lymphoma} 0.92 [0.83-1.07] vs. ADC{sub no} {sub lymphoma} 1.35 [1.10-1.64] P=0.001). Further differentiation between types of metastases was not possible using FA and ADC. There were morphologic differences among the main subtypes of brain metastases/CNS lymphomas. However, due to a high variability of common types of metastases and low specificity, prospective differentiation remained challenging. DTI including FA and ADC was not a reliable tool for differentiation between different histopathological subtypes of brain metastases except for CNS lymphomas showing lower ADC values. Biopsy, surgery and staging remain essential for diagnosis.

  17. Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism

    DEFF Research Database (Denmark)

    Fex Svenningsen, Åsa; Wicher, Grzegorz; Lundqvist, Johan

    2011-01-01

    The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous...... studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons...... whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism....

  18. Comparative antibiogram of coagulase-negative Staphylococci (CNS) associated with subclinical and clinical mastitis in dairy cows.

    Science.gov (United States)

    Bansal, B K; Gupta, D K; Shafi, T A; Sharma, S

    2015-03-01

    The present study was planned to determine the in vitro antibiotic susceptibility of coagulase-negative Staphylococci (CNS) strains isolated from clinical and subclinical cases of mastitis in dairy cows. Antibiotic sensitivity profile will be helpful to recommend early therapy at the field level prior to availability of CST results. The milk samples from cases of clinical mastitis received in Mastitis Laboratory, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana and those of subclinical mastitis collected during routine screening of state dairy farms, were subjected to microbial culture. Identification of CNS organisms was done by standard biochemical tests. Antibiotic sensitivity testing, based on 30 antibiotics belonging to 12 groups, was done on 58 randomly selected CNS isolates (clinical isolates: 41, subclinical isolates: 17). Isolates were highly susceptible to chloramphenicol (98.3%), gentamicin (93.1%), streptomycin (91.4%), linezolid (91.4%), ceftixozime (87.9%), cloxacillin (86.2%), clotrimazole (86.2%), bacitracin (86.2%), enrofloxacin (84.5%) and ceftrioxone + tazobactum (70.7%), while resistance was observed against amoxicillin (77.6%), penicillin (75.9%), ampicillin (74.1%) and cefoperazone (51.7%). Overall, isolates from clinical cases of mastitis had a higher resistance than subclinical isolates. CNS isolates were susceptible to chloramphenicol, gentamicin and streptomycin, while higher resistance was recorded against routinely used penicillin group.

  19. Central nervous system medications and falls risk in men aged 60-75 years

    DEFF Research Database (Denmark)

    Masud, Tahir; Frost, Morten; Ryg, Jesper

    2013-01-01

    Introduction: drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years.......Introduction: drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years....

  20. Glibenclamide for the Treatment of Acute CNS Injury

    Directory of Open Access Journals (Sweden)

    J. Marc Simard

    2013-10-01

    Full Text Available First introduced into clinical practice in 1969, glibenclamide (US adopted name, glyburide is known best for its use in the treatment of diabetes mellitus type 2, where it is used to promote the release of insulin by blocking pancreatic KATP [sulfonylurea receptor 1 (Sur1-Kir6.2] channels. During the last decade, glibenclamide has received renewed attention due to its pleiotropic protective effects in acute CNS injury. Acting via inhibition of the recently characterized Sur1-Trpm4 channel (formerly, the Sur1-regulated NCCa-ATP channel and, in some cases, via brain KATP channels, glibenclamide has been shown to be beneficial in several clinically relevant rodent models of ischemic and hemorrhagic stroke, traumatic brain injury, spinal cord injury, neonatal encephalopathy of prematurity, and metastatic brain tumor. Glibenclamide acts on microvessels to reduce edema formation and secondary hemorrhage, it inhibits necrotic cell death, it exerts potent anti-inflammatory effects and it promotes neurogenesis—all via inhibition of Sur1. Two clinical trials, one in TBI and one in stroke, currently are underway. These recent findings, which implicate Sur1 in a number of acute pathological conditions involving the CNS, present new opportunities to use glibenclamide, a well-known, safe pharmaceutical agent, for medical conditions that heretofore had few or no treatment options.

  1. Similar chemokine receptor profiles in lymphomas with central nervous system involvement - possible biomarkers for patient selection for central nervous system prophylaxis, a retrospective study.

    Science.gov (United States)

    Lemma, Siria A; Pasanen, Anna Kaisa; Haapasaari, Kirsi-Maria; Sippola, Antti; Sormunen, Raija; Soini, Ylermi; Jantunen, Esa; Koivunen, Petri; Salokorpi, Niina; Bloigu, Risto; Turpeenniemi-Hujanen, Taina; Kuittinen, Outi

    2016-05-01

    Central nervous system (CNS) relapse occurs in around 5% of diffuse large B-cell lymphoma (DLBCL) cases. No biomarkers to identify high-risk patients have been discovered. We evaluated the expression of lymphocyte-guiding chemokine receptors in systemic and CNS lymphomas. Immunohistochemical staining for CXCR4, CXCR5, CCR7, CXCL12, and CXCL13 was performed on 89 tissue samples, including cases of primary central nervous system lymphoma (PCNSL), secondary CNS lymphoma (sCNSL), and systemic DLBCL. Also, 10 reactive lymph node samples were included. Immunoelectron microscopy was performed on two PCNSLs, one sCNSL, one systemic DLBCL, and one reactive lymph node samples, and staining was performed for CXCR4, CXCR5, CXCL12, and CXCL13. Chi-square test was used to determine correlations between clinical parameters, diagnostic groups, and chemokine receptor expression. Strong nuclear CXCR4 positivity correlated with systemic DLBCL, whereas strong cytoplasmic CXCR5 positivity correlated with CNS involvement (P = 0.003 and P = 0.039). Immunoelectron microscopy revealed a nuclear CXCR4 staining in reactive lymph node, compared with cytoplasmic and membranous localization seen in CNS lymphomas. We found that CNS lymphoma presented a chemokine receptor profile different from systemic disease. Our findings give new information on the CNS tropism of DLBCL and, if confirmed, may contribute to more effective targeting of CNS prophylaxis among patients with DLBCL. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine.

    Science.gov (United States)

    Boguszewska-Czubara, Anna; Budzynska, Barbara; Skalicka-Wozniak, Krystyna; Kurzepa, Jacek

    2018-05-13

    Matrix metalloproteinases (MMPs) play a key role in remodelling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation and survival. Their importance in variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain and only some pathological ones. Numerous neurodegenerative diseases is a consequence or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development and the progress of these diseases. In present review we discuss the role of metalloproteinase inhibitors, from the well-known natural endogenous tissue inhibitors of metalloproteinases (TIMPs) through exogenous synthetic ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplasctic diseases, the knowledge about the enzymatic system in mammalian brain tissue remain still poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of physiological function of adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries and others. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Role of ATP-binding cassette and solute carrier transporters in erlotinib CNS penetration and intracellular accumulation.

    Science.gov (United States)

    Elmeliegy, Mohamed A; Carcaboso, Angel M; Tagen, Michael; Bai, Feng; Stewart, Clinton F

    2011-01-01

    To study the role of drug transporters in central nervous system (CNS) penetration and cellular accumulation of erlotinib and its metabolite, OSI-420. After oral erlotinib administration to wild-type and ATP-binding cassette (ABC) transporter-knockout mice (Mdr1a/b(-/-), Abcg2(-/-), Mdr1a/b(-/-)Abcg2(-/-), and Abcc4(-/-)), plasma was collected and brain extracellular fluid (ECF) was sampled using intracerebral microdialysis. A pharmacokinetic model was fit to erlotinib and OSI-420 concentration-time data, and brain penetration (P(Brain)) was estimated by the ratio of ECF-to-unbound plasma area under concentration-time curves. Intracellular accumulation of erlotinib was assessed in cells overexpressing human ABC transporters or SLC22A solute carriers. P(Brain) in wild-type mice was 0.27 ± 0.11 and 0.07 ± 0.02 (mean ± SD) for erlotinib and OSI-420, respectively. Erlotinib and OSI-420 P(Brain) in Abcg2(-/-) and Mdr1a/b(-/-)Abcg2(-/-) mice were significantly higher than in wild-type mice. Mdr1a/b(-/-) mice showed similar brain ECF penetration as wild-type mice (0.49 ± 0.37 and 0.04 ± 0.02 for erlotinib and OSI-420, respectively). In vitro, erlotinib and OSI-420 accumulation was significantly lower in cells overexpressing breast cancer resistance protein (BCRP) than in control cells. Only OSI-420, not erlotinib, showed lower accumulation in cells overexpressing P-glycoprotein (P-gp) than in control cells. The P-gp/BCRP inhibitor elacridar increased erlotinib and OSI-420 accumulation in BCRP-overexpressing cells. Erlotinib uptake was higher in OAT3- and OCT2-transfected cells than in empty vector control cells. Abcg2 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Erlotinib and OSI-420 are substrates for SLC22A family members OAT3 and OCT2. Our findings provide a mechanistic basis for erlotinib CNS penetration, cellular uptake, and efflux mechanisms. ©2010 AACR.

  4. Micropituitarism and cortical dysplasia: an unknown association of two uncommon CNS disorders

    International Nuclear Information System (INIS)

    Blinder, G.; Corat-Simon, J.; Hershkovitz, E.

    2001-01-01

    We describe a case of two known pathologies of the CNS in an unusual association: the concomitant presentation of the micropituitarism and cortical dysplasia. To our knowledge, this association is unreported to date. (orig.)

  5. Micropituitarism and cortical dysplasia: an unknown association of two uncommon CNS disorders

    Energy Technology Data Exchange (ETDEWEB)

    Blinder, G. [MAR Bikur Cholim Hospital Jerusalem (MOR-MAR), Jerusalem (Israel); Corat-Simon, J. [Dept. of Radiology, Assaf Harofeh Medical Center, Zrifin, Beer Jakov (Israel); Hershkovitz, E. [Dept. of Pediatrics, Soroka Medical Center, Beer Sheba (Israel)

    2001-06-01

    We describe a case of two known pathologies of the CNS in an unusual association: the concomitant presentation of the micropituitarism and cortical dysplasia. To our knowledge, this association is unreported to date. (orig.)

  6. Leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia : MR imaging findings

    International Nuclear Information System (INIS)

    Kim, Jong Sub; Lee, Sang Kwon; Kim, Tae Hun; Kim, Yong Joo; Kang, Duck Sik; Kwon, Soon Hak; Lee, Keon Soo

    2001-01-01

    To evaluate the MR imaging findings and the usefulness of MR imaging in the diagnosis and follow-up leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia. We retrospectively evaluated the MR imaging findings of eight children with white matter abnormalities on MR out of seventeen acute leukemic patients with various neuropsychiatric symptoms who received intrathecal methotrexate administration, with or without cranial irradiation. In all cases, initial MR was performed within a week of the onset of neuropsychiatric symptoms. Follow-up MR was performed one to sixteen months after initial study, and the MR imaging findings were compared with the initial findings. The initial MR imaging findings were classified into three categories : focal or multifocal white matter abnormalities (3/8), and diffuse white matter abnormalities without enhancement (3/8), and diffuse white matter abnormalities with enhancement (2/8). At follow-up MR, diffuse or focal atrophic changes were noted in all children. White matter abnormalities improved in two out of three patients with focal or multifocal white matter abnormalities. In five with diffuse white matter abnormalities, the extent of these showed no significant change, but contrast enhancement was markedly reduced in two children in whom diffuse white matter abnormalities with enhancement had been demonstrated. In pediatric leukemia, the MR imaging findings of leukoencephalopathy following CNS prophylaxis therapy are variable, but are specific with the clinical history of neuropsychiatric symptoms after intrathecal methotrexate administration, with or without cranial irradiation. The MR imaging is valuable in the diagnosis and follow-up of leukoencephalopathy following CNS prophylaxis therapy in pediatric leukemia

  7. [A review of the effects of lithium on cognitive functions: Effects on the neuropsychiatrically challenged CNS].

    Science.gov (United States)

    Tsaltas, E; Kontis, D

    2009-04-01

    Recent data attribute neuroprotective and neurotrophic actions to lithium, leading to expectations of cognitive enhancement action. This hypothesis is at odds with the predominant view of clinical psychiatr y which, on the basis of older clinical data as well as on subjective reports of lithiumtreated patients, associates lithium with cognitive blurring and specific memory deficits. Review of the older data and their integration with more recent clinical and experimental work on the primary effects of lithium on cognitive functioning led us to two central conclusions: (a) Data on the primary cognitive effects of lithium, considered in their entirety, do not support a picture of serious or long-lasting cognitive decline. On the contrary, recent evidence suggests cognitive enhancement under certain conditions. (b) The conditions which appear to promote the emergence of cognitive enhancement under lithium are conditions of challenge to the cognitive systems, such as increased task difficulty resulting in deterioration in the performance of untreated controls. We are suggesting that alternative challenges to cognitive functioning, which therefore would facilitate the emergence of lithium's cognitive enhancement action, include biological insults to the central nervous system (CNS). This second part of our review of the cognitive effects of lithium therefore focuses on studies of its action on cognitive dysfunction associated with functional or biological challenge to the CNS, such as stress, trauma, neurodegenerative and psychiatric disorders.

  8. The burden and epidemiology of community-acquired central nervous system infections: a multinational study.

    Science.gov (United States)

    Erdem, H; Inan, A; Guven, E; Hargreaves, S; Larsen, L; Shehata, G; Pernicova, E; Khan, E; Bastakova, L; Namani, S; Harxhi, A; Roganovic, T; Lakatos, B; Uysal, S; Sipahi, O R; Crisan, A; Miftode, E; Stebel, R; Jegorovic, B; Fehér, Z; Jekkel, C; Pandak, N; Moravveji, A; Yilmaz, H; Khalifa, A; Musabak, U; Yilmaz, S; Jouhar, A; Oztoprak, N; Argemi, X; Baldeyrou, M; Bellaud, G; Moroti, R V; Hasbun, R; Salazar, L; Tekin, R; Canestri, A; Čalkić, L; Praticò, L; Yilmaz-Karadag, F; Santos, L; Pinto, A; Kaptan, F; Bossi, P; Aron, J; Duissenova, A; Shopayeva, G; Utaganov, B; Grgic, S; Ersoz, G; Wu, A K L; Lung, K C; Bruzsa, A; Radic, L B; Kahraman, H; Momen-Heravi, M; Kulzhanova, S; Rigo, F; Konkayeva, M; Smagulova, Z; Tang, T; Chan, P; Ahmetagic, S; Porobic-Jahic, H; Moradi, F; Kaya, S; Cag, Y; Bohr, A; Artuk, C; Celik, I; Amsilli, M; Gul, H C; Cascio, A; Lanzafame, M; Nassar, M

    2017-09-01

    Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012 and 2014. A total of 2583 patients with CA-CNS infections were included from 37 referral centers in 20 countries. Of these, 477 (18.5%) patients survived with sequelae and 227 (8.8%) died, and 1879 (72.7%) patients were discharged with complete cure. The most frequent infecting pathogens in this study were Streptococcus pneumoniae (n = 206, 8%) and Mycobacterium tuberculosis (n = 152, 5.9%). Varicella zoster virus and Listeria were other common pathogens in the elderly. Although staphylococci and Listeria resulted in frequent infections in immunocompromised patients, cryptococci were leading pathogens in human immunodeficiency virus (HIV)-positive individuals. Among the patients with any proven etiology, 96 (8.9%) patients presented with clinical features of a chronic CNS disease. Neurosyphilis, neurobrucellosis, neuroborreliosis, and CNS tuberculosis had a predilection to present chronic courses. Listeria monocytogenes, Staphylococcus aureus, M. tuberculosis, and S. pneumoniae were the most fatal forms, while sequelae were significantly higher for herpes simplex virus type 1 (p < 0.05 for all). Tackling the high burden of CNS infections globally can only be achieved with effective pneumococcal immunization and strategies to eliminate tuberculosis, and more must be done to improve diagnostic capacity.

  9. Effect of the Putative Lithium Mimetic Ebselen on Brain Myo-Inositol, Sleep, and Emotional Processing in Humans.

    Science.gov (United States)

    Singh, Nisha; Sharpley, Ann L; Emir, Uzay E; Masaki, Charles; Herzallah, Mohammad M; Gluck, Mark A; Sharp, Trevor; Harmer, Catherine J; Vasudevan, Sridhar R; Cowen, Philip J; Churchill, Grant C

    2016-06-01

    Lithium remains the gold standard in treating bipolar disorder but has unwanted toxicity and side effects. We previously reported that ebselen inhibits inositol monophosphatase (IMPase) and exhibits lithium-like effects in animal models through lowering of inositol. Ebselen has been tested in clinical trials for other disorders, enabling us to determine for the first time the effect of a blood-brain barrier-penetrant IMPase inhibitor on human central nervous system (CNS) function. We now report that in a double-blind, placebo-controlled trial with healthy participants, acute oral ebselen reduced brain myo-inositol in the anterior cingulate cortex, consistent with CNS target engagement. Ebselen decreased slow-wave sleep and affected emotional processing by increasing recognition of some emotions, decreasing latency time in the acoustic startle paradigm, and decreasing the reinforcement of rewarding stimuli. In summary, ebselen affects the phosphoinositide cycle and has CNS effects on surrogate markers that may be relevant to the treatment of bipolar disorder that can be tested in future clinical trials.

  10. Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT

    Energy Technology Data Exchange (ETDEWEB)

    Armoogum, Kris S., E-mail: kris.armoogum@nhs.net [Department of Radiotherapy Physics, Royal Derby Hospital, Derby Hospitals NHS Foundation Trust, Uttoxeter Road, Derby DE22 3NE (United Kingdom); Thorp, Nicola [The Clatterbridge Cancer Centre NHS Foundation Trust, Clatterbridge Road, Bebington, Wirral CH63 4JY (United Kingdom)

    2015-04-28

    Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects.

  11. Dosimetric Comparison and Potential for Improved Clinical Outcomes of Paediatric CNS Patients Treated with Protons or IMRT

    Directory of Open Access Journals (Sweden)

    Kris S. Armoogum

    2015-04-01

    Full Text Available Background: We compare clinical outcomes of paediatric patients with CNS tumours treated with protons or IMRT. CNS tumours form the second most common group of cancers in children. Radiotherapy plays a major role in the treatment of many of these patients but also contributes to late side effects in long term survivors. Radiation dose inevitably deposited in healthy tissues outside the clinical target has been linked to detrimental late effects such as neurocognitive, behavioural and vascular effects in addition to endocrine abnormalities and second tumours. Methods: A literature search was performed using keywords: protons, IMRT, CNS and paediatric. Of 189 papers retrieved, 10 were deemed relevant based on title and abstract screening. All papers directly compared outcomes from protons with photons, five papers included medulloblastoma, four papers each included craniopharyngioma and low grade gliomas and three papers included ependymoma. Results: This review found that while proton beam therapy offered similar clinical target coverage, there was a demonstrable reduction in integral dose to normal structures. Conclusions: This in turn suggests the potential for superior long term outcomes for paediatric patients with CNS tumours both in terms of radiogenic second cancers and out-of-field adverse effects.

  12. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

    DEFF Research Database (Denmark)

    Louveau, Antoine; Plog, Benjamin A; Antila, Salli

    2017-01-01

    to the peripheral (CNS-draining) lymph nodes. We speculate on the relationship between the two systems and their malfunction that may underlie some neurological diseases. Although much remains to be investigated, these new discoveries have changed our understanding of mechanisms underlying CNS immune privilege...... and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems....

  13. Neuropsychological screening as a standard of care during discharge from psychiatric hospitalization: the preliminary psychometrics of the CNS Screen.

    Science.gov (United States)

    Levy, Boaz; Celen-Demirtas, Selda; Surguladze, Tinatin; Eranio, Sara; Ellison, James

    2014-03-30

    Cost-prohibitive factors currently prevent a warranted integration of neuropsychological screenings into routine psychiatric evaluations, as a standard of care. To overcome this challenge, the current study examined the psychometric properties of a new computerized measure-the CNS Screen. One hundred and twenty six psychiatric inpatients completed the CNS Screen, the Montreal Cognitive Assessment (MoCA), and the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR₁₆) on the day of hospital discharge. Statistical analysis established convergent validity with a moderate correlation between the self-administered CNS Screen and the clinician-administered MoCA (r=0.64). Discriminant validity was implicated by a non-significant correlation with the QIDS-SR₁₆. Concurrent validity was supported by a moderate, negative correlation with patients' age (r=-0.62). In addition, consistent with previous findings, patients with psychotic disorders exhibited significantly poorer performance on the CNS Screen than patients with a mood disorder. Similarly, patients with a formal disability status scored significantly lower than other patients. The CNS Screen was well tolerated by all patients. With further development, this type of measure may provide a cost-effective approach to expanding neuropsychological screenings on inpatient psychiatric units. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Anatomical Organization of Urocortin 3-Synthesizing Neurons and Immunoreactive Terminals in the Central Nervous System of Non-Human Primates [Sapajus spp.

    Directory of Open Access Journals (Sweden)

    Daniella S. Battagello

    2017-07-01

    Full Text Available Urocortin 3 (UCN3 is a neuropeptide member of the corticotropin-releasing factor (CRF peptide family that acts as a selective endogenous ligand for the CRF, subtype 2 (CRF2 receptor. Immunohistochemistry and in situ hybridization data from rodents revealed UCN3-containing neurons in discrete regions of the central nervous system (CNS, such as the medial preoptic nucleus, the rostral perifornical area (PFA, the medial nucleus of the amygdala and the superior paraolivary nucleus. UCN3-immunoreactive (UCN3-ir terminals are distributed throughout regions that mostly overlap with regions of CRF2 messenger RNA (mRNA expression. Currently, no similar mapping exists for non-human primates. To better understand the role of this neuropeptide, we aimed to study the UCN3 distribution in the brains of New World monkeys of the Sapajus genus. To this end, we analyzed the gene and peptide sequences in these animals and performed immunohistochemistry and in situ hybridization to identify UCN3 synthesis sites and to determine the distribution of UCN3-ir terminals. The sequencing of the Sapajus spp. UCN3-coding gene revealed 88% and 65% identity to the human and rat counterparts, respectively. Additionally, using a probe generated from monkey cDNA and an antiserum raised against human UCN3, we found that labeled cells are mainly located in the hypothalamic and limbic regions. UCN3-ir axons and terminals are primarily distributed in the ventromedial hypothalamic nucleus (VMH and the lateral septal nucleus (LS. Our results demonstrate that UCN3-producing neurons in the CNS of monkeys are phylogenetically conserved compared to those of the rodent brain, that the distribution of fibers agrees with the distribution of CRF2 in other primates and that there is anatomical evidence for the participation of UCN3 in neuroendocrine control in primates.

  15. Melanocortin signaling in the CNS directly regulates circulating cholesterol

    OpenAIRE

    Perez-Tilve, Diego; Hofmann, Susanna M; Basford, Joshua; Nogueiras, Ruben; Pfluger, Paul T; Patterson, James T; Grant, Erin; Wilson-Perez, Hilary E; Granholm, Norman A; Arnold, Myrtha; Trevaskis, James L; Butler, Andrew A; Davidson, William S; Woods, Stephen C; Benoit, Stephen C

    2010-01-01

    Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an impo...

  16. Convention on Nuclear Safety - CNS. Report by the government of the Federal Republic of Germany for the seventh review conference in March/April 2017; Uebereinkommen ueber nukleare Sicherheit. Bericht der Regierung der Bundesrepublik Deutschland fuer die Siebte Ueberpruefungstagung im Maerz/April 2017

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2016-06-22

    The CNS (Convention on Nuclear Safety) report by the government of the Federal Republic of Germany for the seventh review conference in March/April 2017 covers the following topics: Summary of the most important results since the sixth review conference: existing nuclear facilities, frame for legislation and execution, licensing system, regulatory authority, governmental organizations, responsibility of the licensee, priority of safety, financing and personnel, human factors, quality assurance, safety assessment, radiation protection, emergency preparedness, site selection for nuclear facilities, design and construction, operation.

  17. Identification of genetic determinants of the sexual dimorphism in CNS autoimmunity.

    Directory of Open Access Journals (Sweden)

    Frank Bearoff

    Full Text Available Multiple sclerosis (MS is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, with higher prevalence in females, and a strong genetic component. While over 200 MS susceptibility loci have been identified in GWAS, the underlying mechanisms whereby they contribute to disease susceptibility remains ill-defined. Forward genetics approaches using conventional laboratory mouse strains are useful in identifying and functionally dissecting genes controlling disease-relevant phenotypes, but are hindered by the limited genetic diversity represented in such strains. To address this, we have combined the powerful chromosome substitution (consomic strain approach with the genetic diversity of a wild-derived inbred mouse strain. Using experimental allergic encephalomyelitis (EAE, a mouse model of MS, we evaluated genetic control of disease course among a panel of 26 consomic strains of mice inheriting chromosomes from the wild-derived PWD strain on the C57BL/6J background, which models the genetic diversity seen in human populations. Nineteen linkages on 18 chromosomes were found to harbor loci controlling EAE. Of these 19 linkages, six were male-specific, four were female-specific, and nine were non-sex-specific, consistent with a differential genetic control of disease course between males and females. An MS-GWAS candidate-driven bioinformatic analysis using orthologous genes linked to EAE course identified sex-specific and non-sex-specific gene networks underlying disease pathogenesis. An analysis of sex hormone regulation of genes within these networks identified several key molecules, prominently including the MAP kinase family, known hormone-dependent regulators of sex differences in EAE course. Importantly, our results provide the framework by which consomic mouse strains with overall genome-wide genetic diversity, approximating that seen in humans, can be used as a rapid and

  18. Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Deepti Pilli

    2017-06-01

    Full Text Available It is being increasingly recognized that a dysregulation of the immune system plays a vital role in neurological disorders and shapes the treatment of the disease. Aberrant T cell responses, in particular, are key in driving autoimmunity and have been traditionally associated with multiple sclerosis. Yet, it is evident that there are other neurological diseases in which autoreactive T cells have an active role in pathogenesis. In this review, we report on the recent progress in profiling and assessing the functionality of autoreactive T cells in central nervous system (CNS autoimmune disorders that are currently postulated to be primarily T cell driven. We also explore the autoreactive T cell response in a recently emerging group of syndromes characterized by autoantibodies against neuronal cell-surface proteins. Common methodology implemented in T cell biology is further considered as it is an important determinant in their detection and characterization. An improved understanding of the contribution of autoreactive T cells expands our knowledge of the autoimmune response in CNS disorders and can offer novel methods of therapeutic intervention.

  19. An Inverse Optimal Control Approach to Explain Human Arm Reaching Control Based on Multiple Internal Models.

    Science.gov (United States)

    Oguz, Ozgur S; Zhou, Zhehua; Glasauer, Stefan; Wollherr, Dirk

    2018-04-03

    Human motor control is highly efficient in generating accurate and appropriate motor behavior for a multitude of tasks. This paper examines how kinematic and dynamic properties of the musculoskeletal system are controlled to achieve such efficiency. Even though recent studies have shown that the human motor control relies on multiple models, how the central nervous system (CNS) controls this combination is not fully addressed. In this study, we utilize an Inverse Optimal Control (IOC) framework in order to find the combination of those internal models and how this combination changes for different reaching tasks. We conducted an experiment where participants executed a comprehensive set of free-space reaching motions. The results show that there is a trade-off between kinematics and dynamics based controllers depending on the reaching task. In addition, this trade-off depends on the initial and final arm configurations, which in turn affect the musculoskeletal load to be controlled. Given this insight, we further provide a discomfort metric to demonstrate its influence on the contribution of different inverse internal models. This formulation together with our analysis not only support the multiple internal models (MIMs) hypothesis but also suggest a hierarchical framework for the control of human reaching motions by the CNS.

  20. Comparative antibiogram of coagulase-negative Staphylococci (CNS associated with subclinical and clinical mastitis in dairy cows

    Directory of Open Access Journals (Sweden)

    B. K. Bansal

    2015-03-01

    Full Text Available Aim: The present study was planned to determine the in vitro antibiotic susceptibility of coagulase-negative Staphylococci (CNS strains isolated from clinical and subclinical cases of mastitis in dairy cows. Antibiotic sensitivity profile will be helpful to recommend early therapy at the field level prior to availability of CST results. Materials and Methods: The milk samples from cases of clinical mastitis received in Mastitis Laboratory, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana and those of subclinical mastitis collected during routine screening of state dairy farms, were subjected to microbial culture. Identification of CNS organisms was done by standard biochemical tests. Antibiotic sensitivity testing, based on 30 antibiotics belonging to 12 groups, was done on 58 randomly selected CNS isolates (clinical isolates: 41, subclinical isolates: 17. Results: Isolates were highly susceptible to chloramphenicol (98.3%, gentamicin (93.1%, streptomycin (91.4%, linezolid (91.4%, ceftixozime (87.9%, cloxacillin (86.2%, clotrimazole (86.2%, bacitracin (86.2%, enrofloxacin (84.5% and ceftrioxone + tazobactum (70.7%, while resistance was observed against amoxicillin (77.6%, penicillin (75.9%, ampicillin (74.1% and cefoperazone (51.7%. Overall, isolates from clinical cases of mastitis had a higher resistance than subclinical isolates. Conclusion: CNS isolates were susceptible to chloramphenicol, gentamicin and streptomycin, while higher resistance was recorded against routinely used penicillin group.

  1. Modular control of limb movements during human locomotion

    NARCIS (Netherlands)

    Ivanenko, Yuri P; Cappellini, Germana; Dominici, Nadia; Poppele, Richard E; Lacquaniti, Francesco

    2007-01-01

    The idea that the CNS may control complex interactions by modular decomposition has received considerable attention. We explored this idea for human locomotion by examining limb kinematics. The coordination of limb segments during human locomotion has been shown to follow a planar law for walking at

  2. Central nervous system involvement by multiple myeloma

    DEFF Research Database (Denmark)

    Jurczyszyn, Artur; Grzasko, Norbert; Gozzetti, Alessandro

    2016-01-01

    The multicenter retrospective study conducted in 38 centers from 20 countries including 172 adult patients with CNS MM aimed to describe the clinical and pathological characteristics and outcomes of patients with multiple myeloma (MM) involving the central nervous system (CNS). Univariate......, 97% patients received initial therapy for CNS disease, of which 76% received systemic therapy, 36% radiotherapy and 32% intrathecal therapy. After a median follow-up of 3.5 years, the median overall survival (OS) from the onset of CNS involvement for the entire group was 7 months. Untreated...... untreated patients and patients with favorable cytogenetic profile might be prolonged due to systemic treatment and/or radiotherapy. This article is protected by copyright. All rights reserved....

  3. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

    DEFF Research Database (Denmark)

    Louveau, Antoine; Plog, Benjamin A.; Antila, Salli

    2017-01-01

    Recent discoveries of the glymphatic system and of meningeal lymphatic vessels have generated a lot of excitement, along with some degree of skepticism. Here, we summarize the state of the field and point out the gaps of knowledge that should be filled through further research. We discuss...... the glymphatic system as a system that allows CNS perfusion by the cerebrospinal fluid (CSF) and interstitial fluid (ISF). We also describe the recently characterized meningeal lymphatic vessels and their role in drainage of the brain ISF, CSF, CNS-derived molecules, and immune cells from the CNS and meninges...... and CNS drainage. Future studies should explore the communications between the glymphatic system and meningeal lymphatics in CNS disorders and develop new therapeutic modalities targeting these systems....

  4. Validation of In Vitro Cell-Based Human Blood-Brain Barrier Model Using Clinical Positron Emission Tomography Radioligands To Predict In Vivo Human Brain Penetration

    International Nuclear Information System (INIS)

    Mabondzo, A.; Guyot, A.C.; Bottlaender, M.; Deverre, J.R.; Tsaouin, K.; Balimane, P.V.

    2010-01-01

    We have evaluated a novel in vitro cell-based human blood-brain barrier (BBB) model that could predict in vivo human brain penetration for compounds with different BBB permeabilities using the clinical positron emission tomography (PET) data. Comparison studies were also performed to demonstrate that the in vitro cell-based human BBB model resulted in better predictivity over the traditional permeability model in discovery organizations, Caco-2 cells. We evaluated the in vivo BBB permeability of [ 18 F] and [ 11 C]-compounds in humans by PET imaging. The in vivo plasma-brain exchange parameters used for comparison were determined in humans by PET using a kinetic analysis of the radiotracer binding. For each radiotracer, the parameters were determined by fitting the brain kinetics of the radiotracer using a two-tissue compartment model of the ligand-receptor interaction. Bidirectional transport studies with the same compounds as in in vivo studies were carried out using the in vitro cell-based human BBB model as well as Caco-2 cells. The in vitro cell-based human BBB model has important features of the BBB in vivo and is suitable for discriminating between CNS and non-CNS marketed drugs. A very good correlation (r 2 =0.90; P≤0.001) was demonstrated between in vitro BBB permeability and in vivo permeability coefficient. In contrast, a poor correlation (r 2 = 0.17) was obtained between Caco-2 data and in vivo human brain penetration. This study highlights the potential of this in vitro cell-based human BBB model in drug discovery and shows that it can be an extremely effective screening tool for CNS programs. (authors)

  5. Decreased Cognitive/CNS Function in Young Adults at Risk for Hypertension: Effects of Sleep Deprivation

    Directory of Open Access Journals (Sweden)

    James A. McCubbin

    2012-01-01

    Full Text Available Hypertension has been linked to impaired cognitive/CNS function, and some of these changes may precede development of frank essential hypertension. The stress and fatigue of sleep deprivation may exacerbate these cognitive changes in young adults at risk. We hypothesize that individuals at risk for hypertension will show significant declines in cognitive function during a night of sleep deprivation. Fifty-one young adults were recruited for 28-hour total sleep deprivation studies. Hypertension risk was assessed by mildly elevated resting blood pressure and by family history of hypertension. A series of cognitive memory tasks was given at four test sessions across the sleep deprivation period. Although initially comparable in cognitive performance, persons at risk showed larger declines across the night for several indices of working memory, including code substitution, category, and order recall. These results suggest that cognitive/CNS changes may parallel or precede blood pressure dysregulation in the early stages of hypertension development. The role of CNS changes in the etiology of essential hypertension is discussed.

  6. Pygmy squids and giant brains: mapping the complex cephalopod CNS by phalloidin staining of vibratome sections and whole-mount preparations

    DEFF Research Database (Denmark)

    Wollesen, T; Loesel, R; Wanninger, A

    2009-01-01

    experiments are less time-consuming and allow a high throughput of samples. Besides other advantages summarized here, phalloidin reliably labels the entire neuropil of the CNS of all squids, cuttlefish and octopuses investigated. This facilitates high-resolution in toto reconstructions of the CNS...

  7. The cluster [Re6Se8I6]3- penetrates biological membranes: drug-like properties for CNS tumor treatment and diagnosis.

    Science.gov (United States)

    Estrada, Lisbell D; Duran, Elizabeth; Cisterna, Matias; Echeverria, Cesar; Zheng, Zhiping; Borgna, Vincenzo; Arancibia-Miranda, Nicolas; Ramírez-Tagle, Rodrigo

    2018-03-24

    Tumorigenic cell lines are more susceptible to [Re 6 Se 8 I 6 ] 3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.

  8. Information needs of survivors and families after childhood CNS tumor treatment: a population-based study.

    Science.gov (United States)

    Hovén, Emma; Lannering, Birgitta; Gustafsson, Göran; Boman, Krister K

    2018-05-01

    This study examines information needs and satisfaction with provided information among childhood central nervous system (CNS) tumor survivors and their parents. In a population-based sample of 697 adult survivors in Sweden, 518 survivors and 551 parents provided data. Information needs and satisfaction with information were studied using a multi-dimensional standardized questionnaire addressing information-related issues. Overall, 52% of the survivors and 48% of the parents reported no, or only minor, satisfaction with the extent of provided information, and 51% of the survivors expressed a need for more information than provided. The information received was found useful (to some extent/very much) by 53%, while 47% did not find it useful, or to a minor degree only. Obtaining written material was associated with greater satisfaction and usefulness of information. Dissatisfaction with information was associated with longer time since diagnosis, poorer current health status and female sex. The survivors experienced unmet information needs vis-à-vis late effects, illness education, rehabilitation and psychological services. Overall, parents were more dissatisfied than the survivors. These findings have implications for improvements in information delivery. Information in childhood CNS tumor care and follow-up should specifically address issues where insufficiency was identified, and recognize persistent and with time changing needs at the successive stages of long-term survivorship.

  9. [Regularities of fixation of brain serum antibodies from patients with lateral amyotrophic sclerosis in rabbit CNS].

    Science.gov (United States)

    Musaeva, L S; Gannyshkina, I V; Zavalishin, I A; Markova, E D; Ivanova-Smolenskaia, I A

    2002-01-01

    Kuhns' indirect immunofluorescent test was used to study fixation of serum brain antibodies (Ab) of patients with bulbar, cervicothoracic, lumbosacral lateral amyotropic sclerosis (LAS) on brain sections of rabbits. The disease is characterized by formation of brain Ab complementary to various structures of nervous and glial cells, myelin of fibers from different conducting systems, vessels which exhibit both common and individual antigenic properties. It was found that fixation of antineuronal, antimyelin brain Ab of patients with bulbar, cervicothoracic and lumbosacral LAS in different CNS structures varies.

  10. LATE-BREAKING ABSTRACT: Early relapse of non-small cell lung cancer (NSCLC) found after CNS-symptoms

    DEFF Research Database (Denmark)

    Hansen, Niels-Chr. G.; Laursen, Christian B.; Jeppesen, Stefan S.

    2016-01-01

    whether the introduction in 2010 of follow-up by CT of thorax and upper abdomen every three months has reduced the incidence of relapse suspected from CNS-symptoms.Results: All 827 NSCLC patients from Funen completing curative treatment from 2005 to 2013 were included. The total number of relapses found...... or III were found.Conclusion: CT-based follow-up has not reduced the incidence of relapse suspected from CNS-symptoms in stage II-IV, and therefore we suggest routine MR of the brain before curative treatment for this group of patients.Number, fractions(%), and [95%CI]Jan. 2005 - June 2010July 2010 - Dec...... after symptoms within 24 months decreased in the 3½ years after the introduction of CT-based follow-up, p < 0,001 (table), but the total fraction presenting with CNS-symptoms did not change, p = 0.296. Relapses after stage I cancer decreased (p = 0.025), while no differences or changes for stages II...

  11. An Injury Paradigm to Investigate Central Nervous System Repair in Drosophila

    Science.gov (United States)

    Kato, Kentaro; Hidalgo, Alicia

    2013-01-01

    An experimental method has been developed to investigate the cellular responses to central nervous system (CNS) injury using the fruit-fly Drosophila. Understanding repair and regeneration in animals is a key question in biology. The damaged human CNS does not regenerate, and understanding how to promote the regeneration is one of main goals of medical neuroscience. The powerful genetic toolkit of Drosophila can be used to tackle the problem of CNS regeneration. A lesion to the CNS ventral nerve cord (VNC, equivalent to the vertebrate spinal cord) is applied manually with a tungsten needle. The VNC can subsequently be filmed in time-lapse using laser scanning confocal microscopy for up to 24 hr to follow the development of the lesion over time. Alternatively, it can be cultured, then fixed and stained using immunofluorescence to visualize neuron and glial cells with confocal microscopy. Using appropriate markers, changes in cell morphology and cell state as a result of injury can be visualized. With ImageJ and purposely developed plug-ins, quantitative and statistical analyses can be carried out to measure changes in wound size over time and the effects of injury in cell proliferation and cell death. These methods allow the analysis of large sample sizes. They can be combined with the powerful genetics of Drosophila to investigate the molecular mechanisms underlying CNS regeneration and repair. PMID:23567253

  12. Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine

    Science.gov (United States)

    Downey, Luke A.; Loftis, Jennifer M.

    2014-01-01

    Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes – increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID:24485894

  13. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

    Science.gov (United States)

    2014-01-01

    The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiota-derived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3K-dependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85α interaction. Intracerebroventricular GLP-2 augments glucose tolerance, suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110α) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies. PMID:24990862

  14. Proceedings of the 2013 CINP summit: innovative partnerships to accelerate CNS drug discovery for improved patient care.

    Science.gov (United States)

    Phillips, Anthony George; Hongaard-Andersen, Peter; Moscicki, Richard A; Sahakian, Barbara; Quirion, Rémi; Krishnan, K Ranga Rama; Race, Tim

    2014-12-25

    Central nervous system (CNS) diseases and, in particular, mental health disorders, are becoming recognized as the health challenge of the 21(st) century. Currently, at least 10% of the global population is affected by a mental health disorder, a figure that is set to increase year on year. Meanwhile, the rate of development of new CNS drugs has not increased for many years, despite unprecedented levels of investment. In response to this state of affairs, the Collegium Internationale Neuro-Psychopharmacologicum (CINP) convened a summit to discuss ways to reverse this disturbing trend through new partnerships to accelerate CNS drug discovery. The objectives of the Summit were to explore the issues affecting the value chain (i.e. the chain of activities or stakeholders that a company engages in/with to deliver a product to market) in brain research, thereby gaining insights from key stakeholders and developing actions to address unmet needs; to identify achievable objectives to address the issues; to develop action plans to bring about measurable improvements across the value chain and accelerate CNS drug discovery; and finally, to communicate recommendations to governments, the research and development community, and other relevant stakeholders. Summit outputs include the following action plans, aligned to the pressure points within the brain research-drug development value chain: Code of conduct dealing with conflict of interest issues, Prevention, early diagnosis, and treatment, Linking science and regulation, Patient involvement in trial design, definition of endpoints, etc., Novel trial design, Reproduction and confirmation of data, Update of intellectual property (IP) laws to facilitate repurposing and combination therapy (low priority), Large-scale, global patient registries, Editorials on nomenclature, biomarkers, and diagnostic tools, and Public awareness, with brain disease advocates to attend G8 meetings and World Economic Forum (WEF) Annual meetings in

  15. Thermo-siphon Mock-up Test for the HANARO-CNS

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jungwoon; Lee, Kye Hong; Kim, Hark Rho; Kim, Youngki; Kim, Myong Seop; Wu, Sang Ik; Kim, Bong Su

    2006-04-15

    In order to moderate thermal neutrons into cold neutrons, the liquid hydrogen is selected as a moderator for the HANARO CNS. By the non-nuclear heat load and nuclear heat load induced from collision of gamma-ray, beta-ray, and thermal neutrons, the liquid hydrogen in the moderator cell evaporates and flows into the heat exchanger. This evaporated hydrogen gas is liquefied by the cryogenic helium supplied from the helium refrigeration system,, then flows back to the moderator cell. This is so-called two-phase thermo-siphon. The most important point in the stable thermo-siphon is to have the good balance between the cooling capacity of the HRS and the heat load on the moderator cell so as to maintain the stable two-phase liquid level in the moderator cell. Accordingly, for not only the experience of the cryogenic two-phase thermo-siphon but also setup of the operation procedure, the full-scaled mock-up test has been performed using the liquid hydrogen. Through the test, the stable thermo-siphon establishment is confirmed at the cold normal operation; furthermore, the detail design parameter is validated. On top of the normal operation procedure setup, the abnormal operation procedure is settled based on the understanding the abnormal pressure and temperature transient dynamics in the hydrogen system.

  16. Kinetic modelling of [123I]CNS 1261--a potential SPET tracer for the NMDA receptor

    International Nuclear Information System (INIS)

    Erlandsson, Kjell; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S.

    2003-01-01

    N-(1-napthyl)-N'-(3-[ 123 I]-iodophenyl)-N-methylguanidine ([ 123 I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [ 123 I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [ 11 C]-ketamine and [ 18 F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies

  17. Effects of x rays on the morphology and physiology of the CNS blood vessels of mice

    Energy Technology Data Exchange (ETDEWEB)

    Gladysz, J [Akademia Medyczna, Poznan (Poland)

    1974-01-01

    Irradiation of the CNS of mice with 4000 to 7600 R produces transitional disorder of the permeability of vascular walls, followed by a permanent (irreversible) degenerative lesion of blood capillaries and the surrounding astrogial cells. Intensity of this alterations may however not be the same in different terminal blood vessels. It is very likely that the above described lesion appearing in the acute phase can be the main cause of further alterations in the CNS which are observed in late phase of postradiation disease.

  18. Oral Session 03: CNS Risk

    International Nuclear Information System (INIS)

    Narici, Livio; Nelson, Gregory A.

    2014-01-01

    Exposure to space radiation may have impacts on brain function, either during or following missions. It is most important to determine how low doses of protons and high-LET irradiation elicit changes in brain function. Within this framework, the role of oxidative stress should also be assessed, as well as other possible interaction mechanisms involving, e.g., genetic, environmental, and sex-dependent risk factors. The hippocampus is particularly susceptible to radiation. It plays an essential role in memory formation and consolidation and is one of the most investigated brain components for its responses to radiation. The hippocampus is also one of the first brain structures to be damaged in the pathogenesis of Alzheimer's disease, an important potential late impairment following irradiation. In ‘Section 3: CNS risk’, six papers have been presented focused on these issues. For details the reader is directed to the specific papers. Here a very short summary follows

  19. Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

    Directory of Open Access Journals (Sweden)

    Jennifer H Campbell

    2014-12-01

    Full Text Available Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab once a week for three weeks beginning on 28 days post-infection (late. Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS, and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+ in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

  20. Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

    Science.gov (United States)

    Campbell, Jennifer H; Ratai, Eva-Maria; Autissier, Patrick; Nolan, David J; Tse, Samantha; Miller, Andrew D; González, R Gilberto; Salemi, Marco; Burdo, Tricia H; Williams, Kenneth C

    2014-12-01

    Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

  1. Migration, fate and in vivo imaging of stem cells in the CNS

    Czech Academy of Sciences Publication Activity Database

    Syková, Eva

    2009-01-01

    Roč. 16, Suppl.3 (2009), s. 4-4 ISSN 1351-5101. [Congress of the European-Federation-of-Neurological-Societies /13./. 12.09.2009-15.09.2009, Florencie] Institutional research plan: CEZ:AV0Z50390703 Keywords : CNS * ESC Subject RIV: FH - Neurology

  2. Primary CNS lymphoma in nonimmunocompromised patients magnetic resonance study

    International Nuclear Information System (INIS)

    Pena, J.; Fernandez, J.M.; Galarraga, M.I.; Pozo, A.; Montes, A.; Ablanedo, P.

    1995-01-01

    Prymary lymphoma of the CNS (PLCNS) is a relatively infrequent malignant tumor that has become increasingly common over the past decade. The radiological signs, although not pathognomonic, are quite specific and suggestive of the correct diagnosis, thus facilitating therapeutic management. We present six cases of PLCNS in nonimmunocopromised patients studied by MR in our hospital over the past two and a half years. We describe theradiological findings, correlating them with those mentioned in the literature. 14 refs

  3. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1 beta and IL-6

    LENUS (Irish Health Repository)

    Murray, Carol L

    2011-05-17

    Abstract Background Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. Methods ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg\\/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg\\/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined. Results LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg\\/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. Conclusions These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to

  4. Evaluation of CNS activities of aerial parts of Cynodon dactylon Pers. in mice.

    Science.gov (United States)

    Pal, Dilipkumar

    2008-01-01

    The dried extracts of aerial parts of Cynodon dactylon Pers. (Graminae) were evaluated for CNS activities in mice. The ethanol extract of aerial parts of C. dactylon (EECD) was found to cause significant depression in general behavioral profiles in mice. EECD significantly potentiated the sleeping time in mice induced by standard hypnotics viz. pentobarbitone sodium, diazepam, and meprobamate in a dose dependant manner. EECD showed significant analgesic properties as evidenced by the significant reduction in the number of writhes and stretches induced in mice by 1.2% acetic acid solution. It also potentiated analgesia induced by morphine and pethidine in mice. EECD inhibited the onset and the incidence of convulsion in a dose dependent manner against pentylenetetrazole (PTZ)-induced convulsion. The present study indicates that EECD has significant CNS depressant activities.

  5. Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation

    Directory of Open Access Journals (Sweden)

    Ribeiro-da-Silva Alfredo

    2010-11-01

    Full Text Available Abstract Oro-facial pain following injury and infection is frequently observed in dental clinics. While neuropathic pain evoked by injury associated with nerve lesion has an involvement of glia/immune cells, inflammatory hyperalgesia has an exaggerated sensitization mediated by local and circulating immune mediators. To better understand the contribution of central nervous system (CNS glial cells in these different pathological conditions, in this study we sought to characterize functional phenotypes of glial cells in response to trigeminal nerve injury (loose ligation of the mental branch, infection (subcutaneous injection of lipopolysaccharide-LPS and to sterile inflammation (subcutaneous injection of complete Freund's adjuvant-CFA on the lower lip. Each of the three insults triggered a specific pattern of mechanical allodynia. In parallel with changes in sensory response, CNS glial cells reacted distinctively to the challenges. Following ligation of the mental nerve, both microglia and astrocytes in the trigeminal nuclear complex were highly activated, more prominent in the principal sensory nucleus (Pr5 and subnucleus caudalis (Sp5C area. Microglial response was initiated early (days 3-14, followed by delayed astrocytes activation (days 7-28. Although the temporal profile of microglial and astrocyte reaction corresponded respectively to the initiation and chronic stage of neuropathic pain, these activated glial cells exhibited a low profile of cytokine expression. Local injection of LPS in the lower lip skin also triggered a microglial reaction in the brain, which started in the circumventricular organs (CVOs at 5 hours post-injection and diffused progressively into the brain parenchyma at 48 hours. This LPS-induced microglial reaction was accompanied by a robust induction of IκB-α mRNA and pro-inflammatory cytokines within the CVOs. However, LPS induced microglial activation did not specifically occur along the pain signaling pathway. In

  6. 5α-reductases in human physiology: an unfolding story.

    Science.gov (United States)

    Traish, Abdulmaged M

    2012-01-01

    5α-reductases are a family of isozymes expressed in a wide host of tissues including the central nervous system (CNS) and play a pivotal role in male sexual differentiation, development and physiology. A comprehensive literature search from 1970 to 2011 was made through PubMed and the relevant information was summarized. 5α reductases convert testosterone, progesterone, deoxycorticosterone, aldosterone and corticosterone into their respective 5α-dihydro-derivatives, which serve as substrates for 3α-hydroxysteroid dehydrogenase enzymes. The latter transforms these 5α-reduced metabolites into a subclass of neuroactive steroid hormones with distinct physiological functions. The neuroactive steroid hormones modulate a multitude of functions in human physiology encompassing regulation of sexual differentiation, neuroprotection, memory enhancement, anxiety, sleep and stress, among others. In addition, 5α -reductase type 3 is also implicated in the N-glycosylation of proteins via formation of dolichol phosphate. The family of 5α-reductases was targeted for drug development to treat pathophysiological conditions, such as benign prostatic hyperplasia and androgenetic alopecia. While the clinical use of 5α-reductase inhibitors was well established, the scope and the magnitude of the adverse side effects of such drugs, especially on the CNS, is still unrecognized due to lack of knowledge of the various physiological functions of this family of enzymes, especially in the CNS. There is an urgent need to better understand the function of 5α-reductases and the role of neuroactive steroids in human physiology in order to minimize the potential adverse side effects of inhibitors targeting 5α-reductases to treat benign prostatic hyperplasia and androgenic alopecia.

  7. Genetic Separation of Listeria monocytogenes Causing Central Nervous System Infections in Animals

    Directory of Open Access Journals (Sweden)

    Lisandra Aguilar-Bultet

    2018-02-01

    Full Text Available Listeria monocytogenes is a foodborne pathogen that causes abortion, septicemia, gastroenteritis and central nervous system (CNS infections in ruminants and humans. L. monocytogenes strains mainly belong to two distinct phylogenetic groups, named lineages I and II. In general, clinical cases in humans and animals, in particular CNS infections, are caused by lineage I strains, while most of the environmental and food strains belong to lineage II. Little is known about why lineage I is more virulent than lineage II, even though various molecular factors and mechanisms associated with pathogenesis are known. In this study, we have used a variety of whole genome sequence analyses and comparative genomic tools in order to find characteristics that distinguish lineage I from lineage II strains and CNS infection strains from non-CNS strains. We analyzed 225 strains and identified single nucleotide variants between lineages I and II, as well as differences in the gene content. Using a novel approach based on Reads Per Kilobase per Million Mapped (RPKM, we identified 167 genes predominantly absent in lineage II but present in lineage I. These genes are mostly encoding for membrane-associated proteins. Additionally, we found 77 genes that are largely absent in the non-CNS associated strains, while 39 genes are especially lacking in our defined “non-clinical” group. Based on the RPKM analysis and the metadata linked to the L. monocytogenes strains, we identified 6 genes potentially associated with CNS cases, which include a transcriptional regulator, an ABC transporter and a non-coding RNA. Although there is not a clear separation between pathogenic and non-pathogenic strains based on phylogenetic lineages, the presence of the genes identified in our study reveals potential pathogenesis traits in ruminant L. monocytogenes strains. Ultimately, the differences that we have found in our study will help steer future studies in understanding the virulence

  8. Genetic Separation of Listeria monocytogenes Causing Central Nervous System Infections in Animals

    Science.gov (United States)

    Aguilar-Bultet, Lisandra; Nicholson, Pamela; Rychener, Lorenz; Dreyer, Margaux; Gözel, Bulent; Origgi, Francesco C.; Oevermann, Anna; Frey, Joachim; Falquet, Laurent

    2018-01-01

    Listeria monocytogenes is a foodborne pathogen that causes abortion, septicemia, gastroenteritis and central nervous system (CNS) infections in ruminants and humans. L. monocytogenes strains mainly belong to two distinct phylogenetic groups, named lineages I and II. In general, clinical cases in humans and animals, in particular CNS infections, are caused by lineage I strains, while most of the environmental and food strains belong to lineage II. Little is known about why lineage I is more virulent than lineage II, even though various molecular factors and mechanisms associated with pathogenesis are known. In this study, we have used a variety of whole genome sequence analyses and comparative genomic tools in order to find characteristics that distinguish lineage I from lineage II strains and CNS infection strains from non-CNS strains. We analyzed 225 strains and identified single nucleotide variants between lineages I and II, as well as differences in the gene content. Using a novel approach based on Reads Per Kilobase per Million Mapped (RPKM), we identified 167 genes predominantly absent in lineage II but present in lineage I. These genes are mostly encoding for membrane-associated proteins. Additionally, we found 77 genes that are largely absent in the non-CNS associated strains, while 39 genes are especially lacking in our defined “non-clinical” group. Based on the RPKM analysis and the metadata linked to the L. monocytogenes strains, we identified 6 genes potentially associated with CNS cases, which include a transcriptional regulator, an ABC transporter and a non-coding RNA. Although there is not a clear separation between pathogenic and non-pathogenic strains based on phylogenetic lineages, the presence of the genes identified in our study reveals potential pathogenesis traits in ruminant L. monocytogenes strains. Ultimately, the differences that we have found in our study will help steer future studies in understanding the virulence mechanisms of the

  9. Magnetic resonance in the diagnosis of C.N.S. disorders

    International Nuclear Information System (INIS)

    Antunovic, V.; Samardzic, M.; Levic, Z.; Dragutinovic, G.

    2001-01-01

    An introduction of CT and MRI methods resulted in revolutionary changes in the imaging of central nervous systems diseases. The reliability of the use of MRI in the diagnosis of neurological disorders enabled accurate localization, visualization, and anatomical relation and determination of the nature of different pathological processes in the brain and spinal cord. In the past, it had been very difficult to make such precise diagnosis. A result of this fact is a great improvement of treatment of the patients with C.N.S. disorders. The other advantages are excellent possibilities for an assessment of the results of the therapeutical procedures and accurate follow-up of the cases. This was the reason that the authors wanted to make a review of the MRI and clinical characteristic of different neurological and neurosurgical conditions from their wide clinical practice and to determine and illustrate the importance of MRI in the diseases of the brain and spinal cord. (orig.)

  10. Chronic intermittent hypoxia exerts CNS region-specific effects on rat microglial inflammatory and TLR4 gene expression.

    Directory of Open Access Journals (Sweden)

    Stephanie M C Smith

    Full Text Available Intermittent hypoxia (IH during sleep is a hallmark of sleep apnea, causing significant neuronal apoptosis, and cognitive and behavioral deficits in CNS regions underlying memory processing and executive functions. IH-induced neuroinflammation is thought to contribute to cognitive deficits after IH. In the present studies, we tested the hypothesis that IH would differentially induce inflammatory factor gene expression in microglia in a CNS region-dependent manner, and that the effects of IH would differ temporally. To test this hypothesis, adult rats were exposed to intermittent hypoxia (2 min intervals of 10.5% O2 for 8 hours/day during their respective sleep cycles for 1, 3 or 14 days. Cortex, medulla and spinal cord tissues were dissected, microglia were immunomagnetically isolated and mRNA levels of the inflammatory genes iNOS, COX-2, TNFα, IL-1β and IL-6 and the innate immune receptor TLR4 were compared to levels in normoxia. Inflammatory gene expression was also assessed in tissue homogenates (containing all CNS cells. We found that microglia from different CNS regions responded to IH differently. Cortical microglia had longer lasting inflammatory gene expression whereas spinal microglial gene expression was rapid and transient. We also observed that inflammatory gene expression in microglia frequently differed from that in tissue homogenates from the same region, indicating that cells other than microglia also contribute to IH-induced neuroinflammation. Lastly, microglial TLR4 mRNA levels were strongly upregulated by IH in a region- and time-dependent manner, and the increase in TLR4 expression appeared to coincide with timing of peak inflammatory gene expression, suggesting that TLR4 may play a role in IH-induced neuroinflammation. Together, these data indicate that microglial-specific neuroinflammation may play distinct roles in the effects of intermittent hypoxia in different CNS regions.

  11. Monocyte Chemoattractant Protein-1 in the choroid plexus: a potential link between vascular pro-inflammatory mediators and the CNS during peripheral tissue inflammation

    Science.gov (United States)

    Mitchell, K.; Yang, H.-Y. T.; Berk, J. D.; Tran, J. H.; Iadarola, M. J.

    2009-01-01

    During peripheral tissue inflammation, inflammatory processes in the CNS can be initiated by blood-borne pro-inflammatory mediators. The choroid plexus, the site of CSF production, is a highly specialized interface between the vascular system and CNS, and thus, this structure may be an important element in communication between the vascular compartment and the CNS during peripheral tissue inflammation. We investigated the potential participation of the choroid plexus in this process during peripheral tissue inflammation by examining expression of the SCYA2 gene which codes for monocyte chemoattractant protein-1 (MCP-1). MCP-1 protein was previously reported to be induced in a variety of cells during peripheral tissue inflammation. In the basal state, SCYA2 is highly expressed in the choroid plexus as compared to other CNS tissues. During hind paw inflammation, SCYA2 expression was significantly elevated in choroid plexus, whereas it remained unchanged in a variety of brain regions. The SCYA2-expressing cells were strongly associated with the choroid plexus as vascular depletion of blood cells by whole-body saline flush did not significantly alter SCYA2 expression in the choroid plexus. In situ hybridization suggested that the SCYA2-expressing cells were localized to the choroid plexus stroma. To elucidate potential molecular mechanisms of SCYA2 increase, we examined genes in the NF-κβ signaling cascade including TNF-α, IL-1β and IκBα in choroid tissue. Given that we also detected increased levels of MCP-1 protein by ELISA, we sought to identify potential downstream targets of MCP-1 and observed altered expression levels of mRNAs encoding tight junction proteins TJP2 and claudin 5. Finally, we detected a substantial up-regulation of the transcript encoding E-selectin, a molecule which could participate in leukocyte recruitment to the choroid plexus along with MCP-1. Together, these results suggest that profound changes occur in the choroid plexus during

  12. Sodium nitrite induces acute central nervous system toxicity in guinea pigs exposed to systemic cell-free hemoglobin

    International Nuclear Information System (INIS)

    Buehler, Paul W.; Butt, Omer I.; D'Agnillo, Felice

    2011-01-01

    Highlights: → Toxicological implications associated with the use of NaNO 2 therapy to treat systemic cell-free Hb exposure are not well-defined. → Systemic Hb exposure followed by NaNO 2 infusion induces acute CNS toxicities in guinea pigs. → These CNS effects were not reproduced by the infusion of cell-free Hb or NaNO 2 alone. → NaNO 2 -mediated oxidation of cell-free Hb may play a causative role in the observed CNS changes. -- Abstract: Systemic cell-free hemoglobin (Hb) released via hemolysis disrupts vascular homeostasis, in part, through the scavenging of nitric oxide (NO). Sodium nitrite (NaNO 2 ) therapy can attenuate the hypertensive effects of Hb. However, the chemical reactivity of NaNO 2 with Hb may enhance heme- or iron-mediated toxicities. Here, we investigate the effect of NaNO 2 on the central nervous system (CNS) in guinea pigs exposed to systemic cell-free Hb. Intravascular infusion of NaNO 2 , at doses sufficient to alleviate Hb-mediated blood pressure changes, reduced the expression of occludin, but not zona occludens-1 (ZO-1) or claudin-5, in cerebral tight junctions 4 h after Hb infusion. This was accompanied by increased perivascular heme oxygenase-1 expression, neuronal iron deposition, increased astrocyte and microglial activation, and reduced expression of neuron-specific nuclear protein (NeuN). These CNS changes were not observed in animals treated with Hb or NaNO 2 alone. Taken together, these findings suggest that the use of nitrite salts to treat systemic Hb exposure may promote acute CNS toxicity.

  13. The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl+ -redistribution, Tl+ -kinetics and Tl+ -equilibrium distribution.

    Science.gov (United States)

    Wanger, Tim; Scheich, Henning; Ohl, Frank W; Goldschmidt, Jürgen

    2012-07-01

    The potassium (K(+)) analogue thallium (Tl(+)) can be used as a tracer for mapping neuronal activity. However, because of the poor blood-brain barrier (BBB) K(+) -permeability, only minute amounts of Tl(+) enter the brain after systemic injection of Tl(+) -salts like thallium acetate (TlAc). We have recently shown that it is possible to overcome this limitation by injecting animals with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC), that crosses the BBB and releases Tl(+) prior to neuronal or glial uptake. TlDDC can thus be used for mapping CNS K(+) metabolism and neuronal activity. Here, we analyze Tl(+) -kinetics in the rodent brain both experimentally and using simple mathematical models. We systemically injected animals either with TlAc or with TlDDC. Using an autometallographic method we mapped the brain Tl(+) -distribution at various time points after injection. We show that the patterns and kinetics of Tl(+) -redistribution in the brain are essentially the same irrespective of whether animals have been injected with TlAc or TlDDC. Data from modeling and experiments indicate that transmembrane Tl(+) -fluxes in cells within the CNS in vivo equilibrate at similar rates as K(+) -fluxes in vitro. This equilibration is much faster than and largely independent of the equilibration of Tl(+) -fluxes across the BBB. The study provides further proof-of-concept for the use of TlDDC for mapping neuronal activity and CNS K(+) -metabolism. A theoretical guideline is given for the use of K(+) -analogues for imaging neuronal activity with general implications for the use of metal ions in neuroimaging. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  14. Sustainable development through nuclear technology : 29th annual conference of the Canadian Nuclear Society and 32nd CNS/CNA student conference

    International Nuclear Information System (INIS)

    2008-01-01

    The 29th Annual Conference of the Canadian Nuclear Society and 32nd CNS/CNA Student Conference on Sustainable Development through Nuclear Technology was held on June 1-4, 2008 in Toronto, Ontario, Canada. The theme of the conference was 'Nuclear Sustainability'. The central objective of this conference was to provide a forum for exchange of views on how this technical enterprise can best serve the needs of humanity, now and in the future. The renewed global interest in nuclear technology is based on a recognition of its potential to meet economic and environmental targets more favourably than competing technologies. Although many of these attractions are short-term in nature, they stem from a broader potential of nuclear technology to drive all aspects of development (social, environmental, economic) in a sustainable in this area. (author) a terial in support of fuel resources themselves. The conference drew a record attendance of over 450 delegates. Over 100 technical papers were presented within 15 technical sessions, as well as over 30 student papers in 5 sessions. The following list of session titles indicates the diversity of the technical papers: advanced reactors; plant and components; process systems; thermalhydraulics; safety and licensing; hydrogen; human factors; physics; instrumentation and control; environment and waste management; and plant operation. (author)

  15. The CNS connectome of a tadpole larva of Ciona intestinalis (L.) highlights sidedness in the brain of a chordate sibling.

    Science.gov (United States)

    Ryan, Kerrianne; Lu, Zhiyuan; Meinertzhagen, Ian A

    2016-12-06

    Left-right asymmetries in brains are usually minor or cryptic. We report brain asymmetries in the tiny, dorsal tubular nervous system of the ascidian tadpole larva, Ciona intestinalis . Chordate in body plan and development, the larva provides an outstanding example of brain asymmetry. Although early neural development is well studied, detailed cellular organization of the swimming larva's CNS remains unreported. Using serial-section EM we document the synaptic connectome of the larva's 177 CNS neurons. These formed 6618 synapses including 1772 neuromuscular junctions, augmented by 1206 gap junctions. Neurons are unipolar with at most a single dendrite, and few synapses. Some synapses are unpolarised, others form reciprocal or serial motifs; 922 were polyadic. Axo-axonal synapses predominate. Most neurons have ciliary organelles, and many features lack structural specialization. Despite equal cell numbers on both sides, neuron identities and pathways differ left/right. Brain vesicle asymmetries include a right ocellus and left coronet cells.

  16. Transplanting oligodendrocyte progenitors into the adult CNS

    International Nuclear Information System (INIS)

    Franklin, R.J.M.; Blakemore, W.F.; Cambridge Univ.

    1997-01-01

    This review covers a number of aspects of the behaviour of oligodendrocyte progenitors following transplantation into the adult CNS. First, an account is given of the ability of transplanted oligodendrocyte progenitors, grown in tissue culture in the presence of PDGF and bFGF, to extensively remyelinate focal areas of persistent demyelination. Secondly, we describe how transplanted clonal cell lines of oligodendrocyte progenitors will differentiate in to astrocytes as will oligodendrocytes following transplantation into pathological environments in which both oligodendrocytes and astrocytes are absent, thereby manifesting the bipotentially demonstrable in vitro but not during development. Finally, a series of studies examining the migratory behaviour of transplanted oligodendrocyte progenitors (modelled using the oligodendrocyte progenitor cell line CG4) are described. (author)

  17. In Vitro Reconstruction of Neuronal Networks Derived from Human iPS Cells Using Microfabricated Devices.

    Directory of Open Access Journals (Sweden)

    Yuzo Takayama

    Full Text Available Morphology and function of the nervous system is maintained via well-coordinated processes both in central and peripheral nervous tissues, which govern the homeostasis of organs/tissues. Impairments of the nervous system induce neuronal disorders such as peripheral neuropathy or cardiac arrhythmia. Although further investigation is warranted to reveal the molecular mechanisms of progression in such diseases, appropriate model systems mimicking the patient-specific communication between neurons and organs are not established yet. In this study, we reconstructed the neuronal network in vitro either between neurons of the human induced pluripotent stem (iPS cell derived peripheral nervous system (PNS and central nervous system (CNS, or between PNS neurons and cardiac cells in a morphologically and functionally compartmentalized manner. Networks were constructed in photolithographically microfabricated devices with two culture compartments connected by 20 microtunnels. We confirmed that PNS and CNS neurons connected via synapses and formed a network. Additionally, calcium-imaging experiments showed that the bundles originating from the PNS neurons were functionally active and responded reproducibly to external stimuli. Next, we confirmed that CNS neurons showed an increase in calcium activity during electrical stimulation of networked bundles from PNS neurons in order to demonstrate the formation of functional cell-cell interactions. We also confirmed the formation of synapses between PNS neurons and mature cardiac cells. These results indicate that compartmentalized culture devices are promising tools for reconstructing network-wide connections between PNS neurons and various organs, and might help to understand patient-specific molecular and functional mechanisms under normal and pathological conditions.

  18. [Creatine kinase BB and lactate in the cerebrospinal fluid of neonates and infants with perinatal injuries of the CNS].

    Science.gov (United States)

    Alatyrtsev, V V; Iakunin, Iu A; Burkova, A S; Podkopaev, V N; Afonina, L G

    1989-01-01

    A study was made of the content of creatine kinase-BB (CK-BB) and lactate in cerebrospinal fluid (CSF) of 202 neonates and infants with perinatal CNS injuries. The relationship was found between the rise of the CK-BB content and the gravity of perinatal CNS injuries. The highest content of CK-BB in CSF was marked in neonates with cerebral disorders complicated by infectious and inflammatory diseases (pneumonia, sepsis). Within the first 5 days of life, the children of this group demonstrated the relationship between the content of CK-BB and lactate of CSF. The measurement of the content of CK-BB in CSF should be used for early diagnosis, assessment of the gravity and course of perinatal CNS injuries in neonates and in infants.

  19. CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder.

    Directory of Open Access Journals (Sweden)

    Pericles Calias

    Full Text Available A major challenge for the treatment of many central nervous system (CNS disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S. I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b may have broader implications for CNS treatment with biopharmaceuticals.

  20. Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes.

    Science.gov (United States)

    Kaewpoowat, Quanhathai; Salazar, Lucrecia; Aguilera, Elizabeth; Wootton, Susan H; Hasbun, Rodrigo

    2016-06-01

    To describe the clinical manifestations, cerebrospinal fluid (CSF) characteristics, imaging studies and prognostic factors of adverse clinical outcomes (ACO) among adults with herpes simplex virus (HSV) or varicella zoster virus (VZV) CNS infections. Retrospective review of adult patients with positive HSV or VZV polymerase chain reaction on CSF from an observational study of meningitis or encephalitis in Houston, TX (2004-2014), and New Orleans, LA (1999-2008). Ninety-eight adults patients were identified; 25 had encephalitis [20 (20.4 %) HSV, 5 (5.1 %) VZV], and 73 had meningitis [60 (61.1 %) HSV and 13 (13.3 %) VZV]. HSV and VZV had similar presentations except for nausea (P 1 and an encephalitis presentation were independently associated with an ACO. The treatment for HSV meningitis was variable, and all patients had a good clinical outcome. Alpha herpes CNS infections due to HSV and VZV infections have similar clinical and laboratory manifestations. ACO was observed more frequently in those patients with comorbidities and an encephalitis presentation.

  1. Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

    Directory of Open Access Journals (Sweden)

    Fabio Cavaliere

    2016-01-01

    Full Text Available Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson’s disease, and cerebral ischemia.

  2. Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model.

    Directory of Open Access Journals (Sweden)

    Desirée L Salazar

    2010-08-01

    Full Text Available Traumatic spinal cord injury (SCI results in partial or complete paralysis and is characterized by a loss of neurons and oligodendrocytes, axonal injury, and demyelination/dysmyelination of spared axons. Approximately 1,250,000 individuals have chronic SCI in the U.S.; therefore treatment in the chronic stages is highly clinically relevant. Human neural stem cells (hCNS-SCns were prospectively isolated based on fluorescence-activated cell sorting for a CD133(+ and CD24(-/lo population from fetal brain, grown as neurospheres, and lineage restricted to generate neurons, oligodendrocytes and astrocytes. hCNS-SCns have recently been transplanted sub-acutely following spinal cord injury and found to promote improved locomotor recovery. We tested the ability of hCNS-SCns transplanted 30 days post SCI to survive, differentiate, migrate, and promote improved locomotor recovery.hCNS-SCns were transplanted into immunodeficient NOD-scid mice 30 days post spinal cord contusion injury. hCNS-SCns transplanted mice demonstrated significantly improved locomotor recovery compared to vehicle controls using open field locomotor testing and CatWalk gait analysis. Transplanted hCNS-SCns exhibited long-term engraftment, migration, limited proliferation, and differentiation predominantly to oligodendrocytes and neurons. Astrocytic differentiation was rare and mice did not exhibit mechanical allodynia. Furthermore, differentiated hCNS-SCns integrated with the host as demonstrated by co-localization of human cytoplasm with discrete staining for the paranodal marker contactin-associated protein.The results suggest that hCNS-SCns are capable of surviving, differentiating, and promoting improved locomotor recovery when transplanted into an early chronic injury microenvironment. These data suggest that hCNS-SCns transplantation has efficacy in an early chronic SCI setting and thus expands the "window of opportunity" for intervention.

  3. Central Nervous System Vasculitis: Still More Questions than Answers

    Science.gov (United States)

    Alba, Marco A; Espígol-Frigolé, Georgina; Prieto-González, Sergio; Tavera-Bahillo, Itziar; García-Martínez, Ana; Butjosa, Montserrat; Hernández-Rodríguez, José; Cid, Maria C

    2011-01-01

    The central nervous system (CNS) may be involved by a variety of inflammatory diseases of blood vessels. These include primary angiitis of the central nervous system (PACNS), a rare disorder specifically targeting the CNS vasculature, and the systemic vasculitides which may affect the CNS among other organs and systems. Both situations are severe and convey a guarded prognosis. PACNS usually presents with headache and cognitive impairment. Focal symptoms are infrequent at disease onset but are common in more advanced stages. The diagnosis of PACNS is difficult because, although magnetic resonance imaging is almost invariably abnormal, findings are non specific. Angiography has limited sensitivity and specificity. Brain and leptomeningeal biopsy may provide a definitive diagnosis when disclosing blood vessel inflammation and are also useful to exclude other conditions presenting with similar findings. However, since lesions are segmental, a normal biopsy does not completely exclude PACNS. Secondary CNS involvement by systemic vasculitis occurs in less than one fifth of patients but may be devastating. A prompt recognition and aggressive treatment is crucial to avoid permanent damage and dysfunction. Glucocorticoids and cyclophosphamide are recommended for patients with PACNS and for patients with secondary CNS involvement by small-medium-sized systemic vasculitis. CNS involvement in large-vessel vasculitis is usually managed with high-dose glucocorticoids (giant-cell arteritis) or glucocorticoids and immunosuppressive agents (Takayasu’s disease). However, in large vessel vasculitis, where CNS symptoms are usually due to involvement of extracranial arteries (Takayasu’s disease) or proximal portions of intracranial arteries (giant-cell arteritis), revascularization procedures may also have an important role. PMID:22379458

  4. Secretory Products of the Human GI Tract Microbiome and Their Potential Impact on Alzheimer's Disease (AD: Detection of Lipopolysaccharide (LPS in AD Hippocampus

    Directory of Open Access Journals (Sweden)

    Yuhai Zhao

    2017-07-01

    Full Text Available Although the potential contribution of the human gastrointestinal (GI tract microbiome to human health, aging, and disease is becoming increasingly acknowledged, the molecular mechanics and signaling pathways of just how this is accomplished is not well-understood. Major bacterial species of the GI tract, such as the abundant Gram-negative bacilli Bacteroides fragilis (B. fragilis and Escherichia coli (E. coli, secrete a remarkably complex array of pro-inflammatory neurotoxins which, when released from the confines of the healthy GI tract, are pathogenic and highly detrimental to the homeostatic function of neurons in the central nervous system (CNS. For the first time here we report the presence of bacterial lipopolysaccharide (LPS in brain lysates from the hippocampus and superior temporal lobe neocortex of Alzheimer's disease (AD brains. Mean LPS levels varied from two-fold increases in the neocortex to three-fold increases in the hippocampus, AD over age-matched controls, however some samples from advanced AD hippocampal cases exhibited up to a 26-fold increase in LPS over age-matched controls. This “Perspectives” paper will further highlight some very recent research on GI tract microbiome signaling to the human CNS, and will update current findings that implicate GI tract microbiome-derived LPS as an important internal contributor to inflammatory degeneration in the CNS.

  5. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

    International Nuclear Information System (INIS)

    Merchant, Thomas E.; Kiehna, Erin N.; Li Chenghong; Shukla, Hemant; Sengupta, Saikat; Xiong Xiaoping; Gajjar, Amar; Mulhern, Raymond K.

    2006-01-01

    Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had a significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts

  6. Brain MRI screening showing evidences of early central nervous system involvement in patients with systemic sclerosis.

    Science.gov (United States)

    Mohammed, Reem Hamdy A; Sabry, Yousriah Y; Nasef, Amr A

    2011-05-01

    Systemic sclerosis is a multisystem autoimmune collagen disease where structural and functional abnormalities of small blood vessels prevail. Transient ischemic attacks, ischemic stroke, and hemorrhage have been reported as primary consequence of vascular central nervous system affection in systemic sclerosis. Magnetic resonance imaging is considered to be the most sensitive diagnostic technique for detecting symptomatic and asymptomatic lesions in the brain in cases of multifocal diseases. The objective of this study is to detect subclinical as well as clinically manifest cerebral vasculopathy in patients with systemic sclerosis using magnetic resonance imaging. As much as 30 female patients with systemic sclerosis aged 27-61 years old, with disease duration of 1-9 years and with no history of other systemic disease or cerebrovascular accidents, were enrolled. Age-matched female control group of 30 clinically normal subjects, underwent brain magnetic resonance examination. Central nervous system (CNS) involvement in the form of white matter hyperintense foci of variable sizes were found in significantly abundant forms in systemic sclerosis patients on magnetic resonance evaluation than in age-related control group, signifying a form of CNS vasculopathy. Such foci showed significant correlation to clinical features of organic CNS lesion including headaches, fainting attacks and organic depression as well as to the severity of peripheral vascular disease with insignificant correlation with disease duration. In conclusion, subclinical as well as clinically manifest CNS ischemic vasculopathy is not uncommon in systemic sclerosis patients and magnetic resonance imaging is considered a sensitive noninvasive screening tool for early detection of CNS involvement in patients with systemic sclerosis.

  7. Treatment of initial parenchymal central nervous system involvement in systemic aggressive B-cell lymphoma.

    Science.gov (United States)

    Nijland, Marcel; Jansen, Anne; Doorduijn, Jeanette K; Enting, Roelien H; Bromberg, Jacoline E C; Kluin-Nelemans, Hanneke C

    2017-09-01

    Central nervous system (CNS) involvement in systemic B-cell non-Hodgkin lymphoma (B-NHL) at diagnosis (sysCNS) is rare. We investigated the outcome of 21 patients with sysCNS, most commonly diffuse large B-cell lymphoma, treated with high dose methotrexate (HD-MTX) and R-CHOP. The median number of cycles of HD-MTX and R-CHOP was 4 (range 1-8) and 6 (range 0-8), respectively. Consolidative whole brain radiotherapy (WBRT) was given to 33% (7/21) patients. With a median follow-up of 44 months the 3-year progression free survival (PFS) and overall survival (OS) were 45% (95%CI 34-56%) and 49% (95%CI 38-60%), respectively. Over 90% of patients had an unfavorable international prognostic index score, reflected by treatment-related mortality of 19% (4/21) and relapse-related mortality of 28% (6/21). The outcome of these patients was, however, unexpectedly good when compared to secondary CNS relapses. Prospective studies are needed to define the optimal treatment for patients with sysCNS, but its rarity might be challenging.

  8. Immune System Activation and Depression: Roles of Serotonin in the Central Nervous System and Periphery.

    Science.gov (United States)

    Robson, Matthew J; Quinlan, Meagan A; Blakely, Randy D

    2017-05-17

    Serotonin (5-hydroxytryptamine, 5-HT) has long been recognized as a key contributor to the regulation of mood and anxiety and is strongly associated with the etiology of major depressive disorder (MDD). Although more known for its roles within the central nervous system (CNS), 5-HT is recognized to modulate several key aspects of immune system function that may contribute to the development of MDD. Copious amounts of research have outlined a connection between alterations in immune system function, inflammation status, and MDD. Supporting this connection, peripheral immune activation results in changes in the function and/or expression of many components of 5-HT signaling that are associated with depressive-like phenotypes. How 5-HT is utilized by the immune system to effect CNS function and ultimately behaviors related to depression is still not well understood. This Review summarizes the evidence that immune system alterations related to depression affect CNS 5-HT signaling that can alter MDD-relevant behaviors and that 5-HT regulates immune system signaling within the CNS and periphery. We suggest that targeting the interrelationships between immune and 5-HT signaling may provide more effective treatments for subsets of those suffering from inflammation-associated MDD.

  9. Apoptosis of infiltrating T cells in the central nervous system of mice infected with Theiler's murine encephalomyelitis virus

    International Nuclear Information System (INIS)

    Oleszak, Emilia L.; Hoffman, Brad E.; Chang, J. Robert; Zaczynska, Ewa; Gaughan, John; Katsetos, Christos D.; Platsoucas, Chris D.; Harvey, Nile

    2003-01-01

    Theiler murine encephalomyelitis virus (TMEV), DA strain, induces in susceptible strain of mice a biphasic disease consisting of early acute disease followed by late chronic demyelinating disease. Both phases of the disease are associated with inflammatory infiltrates of the central nervous system (CNS). Late chronic demyelinating disease induced by TMEV serves as an excellent model to study human demyelinating disease, multiple sclerosis. During early acute disease, the virus is partially cleared from the CNS by CD3 + T cells. These T cells express Fas, FasL, negligible levels of Bcl-2 proteins and undergo activation-induced cell death as determined by TUNEL assay leading to resolution of the inflammatory response. In contrast, during late chronic demyelinating disease, and despite dense perivascular and leptomeningeal infiltrates, only very few cells undergo apoptosis. Mononuclear cells infiltrating the CNS express Bcl-2. It appears that the lack of apoptosis of T cells during late chronic demyelinating disease leads to the accumulation of these cells in the CNS. These cells may play a role in the pathogenesis of the demyelinating disease

  10. Use of dihydro-isobenzofuran in combination with serotonin reuptake inhibitors for CNS disease e.g. depression, anxiety, bipolar disorder, obsessive compulsory disorder

    DEFF Research Database (Denmark)

    2013-01-01

    NOVELTY - For treatment of a CNS disease in a patient, dihydro-isobenzofuran compound (I) in combination with serotonin reuptake inhibitor, is used. USE - For treatment of CNS disease (claimed) including depression, anxiety, bipolar disorder, obsessive compulsory disorder, post traumatic stress d...

  11. Evaluation of a TaqMan Array Card for Detection of Central Nervous System Infections.

    Science.gov (United States)

    Onyango, Clayton O; Loparev, Vladimir; Lidechi, Shirley; Bhullar, Vinod; Schmid, D Scott; Radford, Kay; Lo, Michael K; Rota, Paul; Johnson, Barbara W; Munoz, Jorge; Oneko, Martina; Burton, Deron; Black, Carolyn M; Neatherlin, John; Montgomery, Joel M; Fields, Barry

    2017-07-01

    Infections of the central nervous system (CNS) are often acute, with significant morbidity and mortality. Routine diagnosis of such infections is limited in developing countries and requires modern equipment in advanced laboratories that may be unavailable to a number of patients in sub-Saharan Africa. We developed a TaqMan array card (TAC) that detects multiple pathogens simultaneously from cerebrospinal fluid. The 21-pathogen CNS multiple-pathogen TAC (CNS-TAC) assay includes two parasites ( Balamuthia mandrillaris and Acanthamoeba ), six bacterial pathogens ( Streptococcus pneumonia e, Haemophilus influenzae , Neisseria meningitidis , Mycoplasma pneumoniae , Mycobacterium tuberculosis , and Bartonella ), and 13 viruses (parechovirus, dengue virus, Nipah virus, varicella-zoster virus, mumps virus, measles virus, lyssavirus, herpes simplex viruses 1 and 2, Epstein-Barr virus, enterovirus, cytomegalovirus, and chikungunya virus). The card also includes human RNase P as a nucleic acid extraction control and an internal manufacturer control, GAPDH (glyceraldehyde-3-phosphate dehydrogenase). This CNS-TAC assay can test up to eight samples for all 21 agents within 2.5 h following nucleic acid extraction. The assay was validated for linearity, limit of detection, sensitivity, and specificity by using either live viruses (dengue, mumps, and measles viruses) or nucleic acid material (Nipah and chikungunya viruses). Of 120 samples tested by individual real-time PCR, 35 were positive for eight different targets, whereas the CNS-TAC assay detected 37 positive samples across nine different targets. The CNS-TAC assays showed 85.6% sensitivity and 96.7% specificity. Therefore, the CNS-TAC assay may be useful for outbreak investigation and surveillance of suspected neurological disease. Copyright © 2017 American Society for Microbiology.

  12. Vacuolating encephalitis in mice infected by human coronavirus OC43

    International Nuclear Information System (INIS)

    Jacomy, Helene; Talbot, Pierre J.

    2003-01-01

    Involvement of viruses in human neurodegenerative diseases and the underlying pathologic mechanisms remain generally unclear. Human respiratory coronaviruses (HCoV) can infect neural cells, persist in human brain, and activate myelin-reactive T cells. As a means of understanding the human infection, we characterized in vivo the neurotropic and neuroinvasive properties of HCoV-OC43 through the development of an experimental animal model. Virus inoculation of 21-day postnatal C57BL/6 and BALB/c mice led to a generalized infection of the whole CNS, demonstrating HCoV-OC43 neuroinvasiveness and neurovirulence. This acute infection targeted neurons, which underwent vacuolation and degeneration while infected regions presented strong microglial reactivity and inflammatory reactions. Damage to the CNS was not immunologically mediated and microglial reactivity was instead a consequence of direct virus-mediated neuronal injury. Although this acute encephalitis appears generally similar to that induced by murine coronaviruses, an important difference rests in the prominent spongiform-like degeneration that could trigger neuropathology in surviving animals

  13. Immune response induction in the central nervous system

    DEFF Research Database (Denmark)

    Owens, Trevor; Babcock, Alicia

    2002-01-01

    The primary function of the immune response is protection of the host against infection with pathogens, including viruses. Since viruses can infect any tissue of the body, including the central nervous system (CNS), it is logical that cells of the immune system should equally have access to all...... tissues. Nevertheless, the brain and spinal cord are noted for their lack of immune presence. Relative to other organ systems, the CNS appears immunologically privileged. Furthermore, when immune responses do occur in the CNS, they are frequently associated with deleterious effects such as inflammatory...

  14. Sodium nitrite induces acute central nervous system toxicity in guinea pigs exposed to systemic cell-free hemoglobin

    Energy Technology Data Exchange (ETDEWEB)

    Buehler, Paul W.; Butt, Omer I. [Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States); D' Agnillo, Felice, E-mail: felice.dagnillo@fda.hhs.gov [Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD (United States)

    2011-06-10

    Highlights: {yields} Toxicological implications associated with the use of NaNO{sub 2} therapy to treat systemic cell-free Hb exposure are not well-defined. {yields} Systemic Hb exposure followed by NaNO{sub 2} infusion induces acute CNS toxicities in guinea pigs. {yields} These CNS effects were not reproduced by the infusion of cell-free Hb or NaNO{sub 2} alone. {yields} NaNO{sub 2}-mediated oxidation of cell-free Hb may play a causative role in the observed CNS changes. -- Abstract: Systemic cell-free hemoglobin (Hb) released via hemolysis disrupts vascular homeostasis, in part, through the scavenging of nitric oxide (NO). Sodium nitrite (NaNO{sub 2}) therapy can attenuate the hypertensive effects of Hb. However, the chemical reactivity of NaNO{sub 2} with Hb may enhance heme- or iron-mediated toxicities. Here, we investigate the effect of NaNO{sub 2} on the central nervous system (CNS) in guinea pigs exposed to systemic cell-free Hb. Intravascular infusion of NaNO{sub 2}, at doses sufficient to alleviate Hb-mediated blood pressure changes, reduced the expression of occludin, but not zona occludens-1 (ZO-1) or claudin-5, in cerebral tight junctions 4 h after Hb infusion. This was accompanied by increased perivascular heme oxygenase-1 expression, neuronal iron deposition, increased astrocyte and microglial activation, and reduced expression of neuron-specific nuclear protein (NeuN). These CNS changes were not observed in animals treated with Hb or NaNO{sub 2} alone. Taken together, these findings suggest that the use of nitrite salts to treat systemic Hb exposure may promote acute CNS toxicity.

  15. Evaluation of cerebral perfusion in patients with neuropsychiatric systemic lupus erythematosus using 123I-IMP SPECT

    International Nuclear Information System (INIS)

    Yoshida, Atsuko; Shishido, Fumio; Kato, Kazuo; Watanabe, Hiroshi; Seino, Osamu

    2007-01-01

    In the course of systemic lupus erythematosus (SLE), central nervous system (CNS) complications occur at a high frequency. An accurate diagnosis of CNS lupus, differentiated from secondary CNS involvement, is difficult. CNS lupus is indicative of advancing primary disease and is treated by steroid pulse therapy or increased dosage of steroids. In contrast, if symptoms are caused by secondary CNS complications, it is possible to observe or treat these complications using symptomatic therapy. We examined whether quantitative cerebral blood flow (CBF) measured using cerebral perfusion single photon emission computed tomography (SPECT) can be used to differentiate CNS lupus from secondary CNS involvement. We divided 18 SLE patients with CNS symptoms into a CNS lupus group and a non-CNS lupus group, and then compared the mean cerebral blood flow (mCBF) of each group of patients. SPECT was performed with N-isopropyl-p-[ 123 I] iodoamphetamine (IMP), with quantitation carried out by table look-up and autoradiographic methods. The mCBF of both groups was decreased; however, the mCBF of patients with CNS lupus was significantly lower than that of non-CNS lupus patients. Quantitative CBF may provide a useful tool to distinguish CNS lupus from non-CNS lupus. (author)

  16. Human Adaptive Mechatronics and Human-System Modelling

    Directory of Open Access Journals (Sweden)

    Satoshi Suzuki

    2013-03-01

    Full Text Available Several topics in projects for mechatronics studies, which are 'Human Adaptive Mechatronics (HAM' and 'Human-System Modelling (HSM', are presented in this paper. The main research theme of the HAM project is a design strategy for a new intelligent mechatronics system, which enhances operators' skills during machine operation. Skill analyses and control system design have been addressed. In the HSM project, human modelling based on hierarchical classification of skills was studied, including the following five types of skills: social, planning, cognitive, motion and sensory-motor skills. This paper includes digests of these research topics and the outcomes concerning each type of skill. Relationships with other research activities, knowledge and information that will be helpful for readers who are trying to study assistive human-mechatronics systems are also mentioned.

  17. A project proposal for the implementation of Intensity Modulated Radiation Therapy (IMRT) for treatment of tumors of the central nervous system (CNS)

    International Nuclear Information System (INIS)

    Alert Silva, Jose; Chon Rivas, Ivon; Ascension Ibarra, Yudy; Yanez Lopez, Yaima; Rodriguez Zayas, Michel; Diaz Moreno, Rogelio

    2009-01-01

    Radiotherapy, together with the surgery, one of the essential therapeutic tools in the treatment of CNS tumors. The use of radiation, can be severe sequelae affecting quality of life of the patient, organs at risk receiving high dose and advanced technique of IMRT treatment planning and allows treatments shaped fields, especially when the target of radiation is irregular, with fewer side effects by limiting the dose in the tumor tissues and organs at risk and to allow us to increase the doses in the tumor .. So we decided to develop a protocol for the implementation of IMRT, taking into account that we have the appropriate equipment, trained staff to develop this technique. The main objective of this proposal is to allow us to establish the parameters necessary to perform IMRT, and then escalate the dose of radiation to the tumor, with reduced toxicity to healthy tissues. Inclusion criteria. It included 6 patients with histological diagnosis of CNS tumors, specifically astrocytomas grade II, III and IV, glioblastoma multiforme, where radiation is the main treatment, or associated with surgery. It excludes patients who have previously received radiation therapy or are unable to receive treatment without having movements that do not suffer another debilitating disease and to sign informed consent. Be held position and will be used as masks thermo deformed stun, then planning CT performed in all cases. Be designed later volumes (GTV, CTV and PTV, and OR, as established by the ICRU reports 52 and 60, the IAEA), will define the dose, and restrictions on healthy tissue technique is defined treatment according proposed objectives in the planning system. Once approved, is made conventional simulation, verification of the treatment plan on your computer with web plates and implementation of treatment in 1220 of INOR LINAC. Be made patient-specific quality controls and verification of DRR plan once a week for each patient treated. Monitoring will be conducted weekly during

  18. Prediction of brain target site concentrations on the basis of CSF PK : impact of mechanisms of blood-to-brain transport and within brain distribution

    NARCIS (Netherlands)

    Westerhout, J.

    2014-01-01

    In the development of drugs for the treatment of central nervous system (CNS) disorders, the prediction of human CNS drug action is a big challenge. Direct measurement of brain extracellular fluid (brainECF) concentrations is highly restricted in human. Therefore, unbound drug concentrations in

  19. Functional Properties of Human Stem Cell-Derived Neurons in Health and Disease

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    Jason P. Weick

    2016-01-01

    Full Text Available Stem cell-derived neurons from various source materials present unique model systems to examine the fundamental properties of central nervous system (CNS development as well as the molecular underpinnings of disease phenotypes. In order to more accurately assess potential therapies for neurological disorders, multiple strategies have been employed in recent years to produce neuronal populations that accurately represent in vivo regional and transmitter phenotypes. These include new technologies such as direct conversion of somatic cell types into neurons and glia which may accelerate maturation and retain genetic hallmarks of aging. In addition, novel forms of genetic manipulations have brought human stem cells nearly on par with those of rodent with respect to gene targeting. For neurons of the CNS, the ultimate phenotypic characterization lies with their ability to recapitulate functional properties such as passive and active membrane characteristics, synaptic activity, and plasticity. These features critically depend on the coordinated expression and localization of hundreds of ion channels and receptors, as well as scaffolding and signaling molecules. In this review I will highlight the current state of knowledge regarding functional properties of human stem cell-derived neurons, with a primary focus on pluripotent stem cells. While significant advances have been made, critical hurdles must be overcome in order for this technology to support progression toward clinical applications.

  20. Biomarkers for CNS involvement in pediatric lupus

    Science.gov (United States)

    Rubinstein, Tamar B; Putterman, Chaim; Goilav, Beatrice

    2015-01-01

    CNS disease, or central neuropsychiatric lupus erythematosus (cNPSLE), occurs frequently in pediatric lupus, leading to significant morbidity and poor long-term outcomes. Diagnosing cNPSLE is especially difficult in pediatrics; many current diagnostic tools are invasive and/or costly, and there are no current accepted screening mechanisms. The most complicated aspect of diagnosis is differentiating primary disease from other etiologies; research to discover new biomarkers is attempting to address this dilemma. With many mechanisms involved in the pathogenesis of cNPSLE, biomarker profiles across several modalities (molecular, psychometric and neuroimaging) will need to be used. For the care of children with lupus, the challenge will be to develop biomarkers that are accessible by noninvasive measures and reliable in a pediatric population. PMID:26079959

  1. Disubstituted thiourea derivatives and their activity on CNS: synthesis and biological evaluation.

    Science.gov (United States)

    Stefanska, Joanna; Szulczyk, Daniel; Koziol, Anna E; Miroslaw, Barbara; Kedzierska, Ewa; Fidecka, Sylwia; Busonera, Bernardetta; Sanna, Giuseppina; Giliberti, Gabriele; La Colla, Paolo; Struga, Marta

    2012-09-01

    A series of new thiourea derivatives of 1,2,4-triazole have been synthesized. The difference in structures of obtained compounds are directly connected with the kind of isothiocyanate (aryl/alkyl). The (1)H NMR, (13)C NMR, MS methods were used to confirm structures of obtained thiourea derivatives. The molecular structure of (1, 17) was determined by an X-ray analysis. Two of the new compounds (8 and 14) were tested for their pharmacological activity on animal central nervous system (CNS) in behavioural animal tests. The results presented in this work indicate the possible involvement of the serotonergic system in the activity of 8 and 14. In the case of 14 is also a possible link between its activity and the endogenous opioid system. All obtained compounds were tested for antibacterial activity against gram-positive cocci, gram-negative rods and antifungal activity. Compounds (1, 2, 5, 7, 9) showed significant inhibition against gram-positive cocci. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Selected compounds (1-13) were examined for cytotoxicity, antitumor, and anti-HIV activity. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  2. [Structural CNS abnormalities responsible for coincidental occurrence of endocrine disorders, epilepsy and psychoneurologic disorders in children and adolescents].

    Science.gov (United States)

    Starzyk, Jerzy; Kwiatkowski, Stanisław; Kaciński, Marek; Kroczka, Sławomir; Wójcik, Małgorzata

    2010-01-01

    In the population of children and adolescents, epilepsy affects 0.5-1% of individuals; approximately 3% of general population suffer from non-epileptic seizures, while endocrine disorders are several times more frequent. All of the above factors result in a relatively common non-accidental occurrence of endocrine disorders, epilepsy and neuropsychiatric disorders. However, structural central nervous system (CNS) abnormalities that cause both endocrine and neurologic disorders seem to be markedly less common. No reports addressing this problem are available in the literature. 1) Assessment of the frequency of non-coincidental occurrence of epilepsy and endocrine disorders in inpatients and outpatients with structural CSN abnormalities managed in Department Endocrinology. 2) Presentation of diagnostic and therapeutic difficulties in these patients, and 3) An attempt at defining a common etiology of both disorders. A retrospective analysis of the medical records of the patients with coincidence of endocrine disorders and epilepsy and psycho-neurologic disorders (treated in Chair and Department of Children's and Adolescents Neurology, University Children's Hospital of Krakow or in another pediatric neurology center) and with organic CNS abnormalities (treated or followed up as inpatients and outpatient of Department of Pediatric Surgery, Children's University Hospital of Krakow, was performed. The patients were selected from among several thousands of children treated as inpatients and outpatients of the Department. Various forms of symptomatic and idiopathic epilepsy and other psychoneurological disorders (disorders of behavior and emotions, obsession-compulsion syndromes, stereotypias, aggression, compulsive ideas and movements, anorexia or hypothalamic obesity) coincident with one or more endocrine disorders such as precocious or delayed puberty, multihormonal pituitary deficiency, panhypopituitarism and secondary hypothyroidism were detected in 42 patients with

  3. Prophylactic CNS therapy in childhood leukemia. Randomized controlled study of high-dose intravenous methotrexate and cranial irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Yokoyama, Takashi; Hiyoshi, Yasuhiko [Kurume Univ., Fukuoka (Japan). School of Medicine; Fujimoto, Takeo

    1982-12-01

    This study was designed to evaluate the efficacy of CNS-prophylaxis with high-dose methotrexate (MTX). Seventy children with previously untreated acute lymphoblastic leukemia (ALL) entered to this study between July 1978 and December 1980. According to initial white blood count (WBC), they were stratified to induce remission with; vincristine and prednine in low initial WBC ( lt 25,000/mm/sup 3/) group and these two agents plus adriamycin in high initial WBC ( gt 25,000/mm/sup 3/) group. After inducing remission, 62 children who achieved CR, received different CNS-prophlaxis; using a regimen of three doses of weekly high-dose MTX (1,000 mg/m/sup 2/) 6-hour infusion, which was repeated every 12 weeks-Group A (n = 14); high-dose MTX followed by 2400 rad cranial irradiation plus three doses of i.t. MT X-Group B (n = 15), 2400 rad cranial irradiation plus three doses of i.t. MTX-Group C (n = 16), and in 17 patients with high initial WBC, same as in Group A-Group D (n = 17). During an intravenous 6-h infusion of MTX at a dose of 1,000 mg/m/sup 2/, the CSF concentration of MTX rose to 2.3 +- 2.4 x 10/sup -6/M after initiation of infusion and remained in 10/sup -7/ M level for 48 hours. CNS-leukemia terminated complete remission in one of 14 children in Group A, two of 15 in Group B, two of 16 in Group C and two of 17 in Group D. The cumulative incidence of CNS-leukemia at 20 months calculated by the technique of Kaplan and Meier was 0% in Group A, 18.1% in Group B, 7.1% in Group C and 50.8% in Group D. There was no statistical difference among Groups A, B and C. These data suggested that CNS-prophylaxis with high-dose intravenous MTX was effective as well as 2400 rad cranial irradiation plus three doses of i.t. MTX in childhood ALL with low initial WBC.

  4. FORMATION OF THE INITIAL DISTRIBUTION OF PLASMA COMPONENTS ON THE PHASE PLANE OF LARGE PARTICLES METHOD IN ELECTRIC ARC SYNTHESIS CNS

    Directory of Open Access Journals (Sweden)

    G. V. Abramov

    2014-01-01

    Full Text Available The article deals with the modeling of charged particles in a multicomponent plasma of electric arc discharge with binary collisions in the synthesis of carbon nanostructures (CNS. One of the common methods of obtaining the quality of fullerenes and nanotubes is arc synthesis under inert gas (helium. The determination of the necessary conditions and the mechanism of formation of carbon clusters in the plasma forming set CNS will more effectively and efficiently manage this process. Feature of the problem is that in a plasma arc discharge is a large number of particle interactions and on the cathode surface. Due to the high temperatures and high energy concentration in plasma detailed experimental investigation difficult to carry out. With the aim of avoiding difficult and costly physical experiments developed numerical methods for the analysis of plasma processes. In this article to solve a system of equations of Maxwell - Boltzmann basis for the authors had taken the method of large particles, which reduces the amount of computation and reduce the demands on computing resources. The authors cites the general design scheme of the large particles, and the algorithm of particle distribution of a multicomponent plasma in the phase plane at the initial time. In conclusion, the author argues that the results in the future will define the zone satisfies the energy conditions, the probability of formation of a plasma cluster groups of carbon involved in the synthesis of the CNS.

  5. Microglia - insights into immune system structure, function, and reactivity in the central nervous system

    DEFF Research Database (Denmark)

    Wirenfeldt, Martin; Babcock, Alicia A; Vinters, Harry V

    2011-01-01

    Microglia are essential cellular components of a well-functioning central nervous system (CNS). The development and establishment of the microglial population differs from the other major cell populations in the CNS i.e. neurons and macroglia (astrocytes and oligodendrocytes). This different onto...

  6. THE SIGNIFICANCE OF LESIONS IN PERIPHERAL GANGLIA IN CHIMPANZEE AND IN HUMAN POLIOMYELITIS

    Science.gov (United States)

    Bodian, David; Howe, Howard A.

    1947-01-01

    1. The peripheral ganglia of eighteen inoculated chimpanzees and thirteen uninoculated controls, and of eighteen fatal human poliomyelitis cases, were studied for histopathological evidence of the route of transmission of virus from the alimentary tract to the CNS. 2. Lesions thought to be characteristic of poliomyelitis in inoculated chimpanzees could not be sharply differentiated from lesions of unknown origin in uninoculated control animals. Moreover, although the inoculated animals as a group, in comparison with the control animals, had a greater number of infiltrative lesions in sympathetic as well as in sensory ganglia, it was not possible to make satisfactory correlations between the distribution of these lesions and the routes of inoculation. 3. In sharp contrast with chimpanzees, the celiac and stellate ganglia of the human poliomyelitis cases were free of any but insignificant infiltrative lesions. Lesions in human trigeminal and spinal sensory ganglia included neuronal damage as well as focal and perivascular inflitrative lesions, as is well known. In most ganglia, as in monkey and chimpanzee sensory ganglia, these were correlated in intensify with the degree of severity of lesions in the region of the CNS receiving their axons. This suggested that lesions in sensory ganglia probably resulted from spread of virus centrifugally from the CNS, in accord with considerable experimental evidence. 4. Two principal difficulties in the interpretation of histopathological findings in peripheral ganglia were revealed by this study. The first is that the specificity of lesions in sympathetic ganglia has not been established beyond doubt as being due to poliomyelitis. The second is that the presence of characteristic lesions in sensory ganglia does not, and cannot, reveal whether the virus reached the ganglia from the periphery or from the central nervous system, except in very early preparalytic stages or in exceptional cases of early arrest of virus spread and of

  7. Kynurenines in CNS disease: regulation by inflammatory cytokines

    Science.gov (United States)

    Campbell, Brian M.; Charych, Erik; Lee, Anna W.; Möller, Thomas

    2014-01-01

    The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the “neurotoxic” and “neuroprotective” arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders. PMID:24567701

  8. Central nervous system systemic lupus erythematosus in children

    International Nuclear Information System (INIS)

    Osborn, A.G.; Boyer, R.S.

    1989-01-01

    Ischemic neurologic events and neuropsychiatric disorders occur in approximately 70% of patients with systematic lupus erythematosus (SLE). The CT and MR findings in adults with central nervous system (CNS) SLE have been described, but to the authors' knowledge no pediatric series has been reported. The MR and CT findings in four children with CNS SLE are compared with those reported in adults. Large infarcts are less frequent in children than in adults with CNS SLE, while multiple small infarctions and white matter lesions are more common. These findings in children who have no obvious source of emboli, intracardiac shunt, or history of trauma should raise the suspicion of SLE

  9. Identification of connectivity in human motor control: exciting the afferent pathways

    NARCIS (Netherlands)

    Campfens, S.F.

    2014-01-01

    Motor control involves various parts of the central nervous system (CNS) and requires the exchange of information between neural populations in the CNS. Information exchange in facilitated by the formation of functional networks between populations of was localized at the sensorimotor area

  10. Adults with suspected central nervous system infection: A prospective study of diagnostic accuracy.

    Science.gov (United States)

    Khatib, Ula; van de Beek, Diederik; Lees, John A; Brouwer, Matthijs C

    2017-01-01

    To study the diagnostic accuracy of clinical and laboratory features in the diagnosis of central nervous system (CNS) infection and bacterial meningitis. We included consecutive adult episodes with suspected CNS infection who underwent cerebrospinal fluid (CSF) examination. The reference standard was the diagnosis classified into five categories: 1) CNS infection; 2) CNS inflammation without infection; 3) other neurological disorder; 4) non-neurological infection; and 5) other systemic disorder. Between 2012 and 2015, 363 episodes of suspected CNS infection were included. CSF examination showed leucocyte count >5/mm 3 in 47% of episodes. Overall, 89 of 363 episodes were categorized as CNS infection (25%; most commonly viral meningitis [7%], bacterial meningitis [7%], and viral encephalitis [4%]), 36 (10%) episodes as CNS inflammatory disorder, 111 (31%) as systemic infection, in 119 (33%) as other neurological disorder, and 8 (2%) as other systemic disorders. Diagnostic accuracy of individual clinical characteristics and blood tests for the diagnosis of CNS infection or bacterial meningitis was low. CSF leucocytosis differentiated best between bacterial meningitis and other diagnoses (area under the curve [AUC] 0.95) or any neurological infection versus other diagnoses (AUC 0.93). Clinical characteristics fail to differentiate between neurological infections and other diagnoses, and CSF analysis is the main contributor to the final diagnosis. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

  11. Metastatic Ewing's sarcoma to the skull: CNS involvement excluded by MRI

    International Nuclear Information System (INIS)

    Taets ven Amerongen, A.H.M.; Kaiser, M.C.; Waal, F.C. de

    1987-01-01

    A case of metastatic Ewing's sarcoma to the skull is presented, demonstrating the superiority of magnetic resonance imaging over other imaging modalities to exclude CNS involvement. Precise delineation of different tumor components in extradural location contained in an intact dural rim together with compressed cortex showing no signs of tumorous involvement constituted an MRI appearance allowing us to exclude tumor outgrowth into the brain. (orig.)

  12. Kinetic modelling of [{sup 123}I]CNS 1261--a potential SPET tracer for the NMDA receptor

    Energy Technology Data Exchange (ETDEWEB)

    Erlandsson, Kjell E-mail: k.erlandsson@nucmed.ucl.ac.uk; Bressan, Rodrigo A.; Mulligan, Rachel S.; Gunn, Roger N; Cunningham, Vincent J.; Owens, Jonathan; Wyper, David; Ell, Peter J.; Pilowsky, Lyn S

    2003-05-01

    N-(1-napthyl)-N'-(3-[{sup 123}I]-iodophenyl)-N-methylguanidine ([{sup 123}I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [{sup 123}I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [{sup 11}C]-ketamine and [{sup 18}F]-memantine PET studies . These data provide a methodological basis for further direct in vivo challenge studies.

  13. Inflammation in the CNS and Th17 Responses Are Inhibited by IFN-{gamma}-Induced IL-18 Binding Protein

    DEFF Research Database (Denmark)

    Millward, Jason M; Pedersen, Morten Løbner; Wheeler, Rachel D

    2010-01-01

    Inflammatory responses are essential for immune protection but may also cause pathology and must be regulated. Both Th1 and Th17 cells are implicated in the pathogenesis of autoimmune inflammatory diseases, such as multiple sclerosis. We show in this study that IL-18-binding protein (IL-18bp......), the endogenous inhibitor of the Th1-promoting cytokine IL-18, is upregulated by IFN-gamma in resident microglial cells in the CNS during multiple sclerosis-like disease in mice. Test of function by overexpression of IL-18bp in the CNS using a viral vector led to marked reduction in Th17 responses and robust...... inhibition of incidence, severity, and histopathology of disease, independently of IFN-gamma. The disease-limiting action of IL-18bp included suppression of APC-derived Th17-polarizing cytokines. IL-18bp thus acts as a sensor for IFN-gamma and can regulate both Th1 and Th17 responses in the CNS....

  14. Immune cell entry to the CNS--a focus for immunoregulation of EAE

    DEFF Research Database (Denmark)

    Owens, T; Tran, E; Hassan-Zahraee, M

    1999-01-01

    -requirement then to prove such a role. The point that emerges is that cytokine production in the CNS parenchyma is itself dependent on the prior infiltration of immune cells, and that without immune cell entry, EAE does not occur. This identifies events at the BBB, and in particular in the perivascular space, as critical...

  15. The Lifespan and Turnover of Microglia in the Human Brain

    Directory of Open Access Journals (Sweden)

    Pedro Réu

    2017-07-01

    Full Text Available The hematopoietic system seeds the CNS with microglial progenitor cells during the fetal period, but the subsequent cell generation dynamics and maintenance of this population have been poorly understood. We report that microglia, unlike most other hematopoietic lineages, renew slowly at a median rate of 28% per year, and some microglia last for more than two decades. Furthermore, we find no evidence for the existence of a substantial population of quiescent long-lived cells, meaning that the microglia population in the human brain is sustained by continuous slow turnover throughout adult life.

  16. Adult central nervous system

    International Nuclear Information System (INIS)

    Sutton, M.L.

    1985-01-01

    Historically, the adult central nervous system (CNS) was regarded as relatively immune to the effects of ionising radiation, and the recognition of the CNS as a radio-vulnerable structure occurred later than was the case for many other tissues. Increasingly precise knowledge of the time-dose-volume relationships for CNS tolerance has had two important consequences: (1) it has permitted the avoidance of catastrophic and usually lethal late effects in the brain and spinal cord when these tissues are unavoidably irradiated during the treatment of adjacent non-CNS tumours, and (2) it has encouraged referral for irradiation of certain technically benign lesions which, although compatible with prolonged survival, represent a continuing threat to the patient - for example arteriovenous malformations, pituitary adenomas, and some meningiomas. Many of these can now be controlled for very long periods following radiation doses consistent with the long-term functional integrity of the CNS

  17. The burden and epidemiology of community-acquired central nervous system infections

    DEFF Research Database (Denmark)

    Erdem, H; Inan, A; Guven, E

    2017-01-01

    Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012...

  18. Convulsant bicuculline modifies CNS muscarinic receptor affinity

    Directory of Open Access Journals (Sweden)

    Rodríguez de Lores Arnaiz Georgina

    2006-04-01

    Full Text Available Abstract Background Previous work from this laboratory has shown that the administration of the convulsant drug 3-mercaptopropionic acid (MP, a GAD inhibitor, modifies not only GABA synthesis but also binding of the antagonist [3H]-quinuclidinyl benzilate ([3H]-QNB to central muscarinic receptors, an effect due to an increase in affinity without modifications in binding site number. The cholinergic system has been implicated in several experimental epilepsy models and the ability of acetylcholine to regulate neuronal excitability in the neocortex is well known. To study the potential relationship between GABAergic and cholinergic systems with seizure activity, we analyzed the muscarinic receptor after inducing seizure by bicuculline (BIC, known to antagonize the GABA-A postsynaptic receptor subtype. Results We analyzed binding of muscarinic antagonist [3H]-QNB to rat CNS membranes after i.p. administration of BIC at subconvulsant (1.0 mg/kg and convulsant (7.5 mg/kg doses. Subconvulsant BIC dose failed to develop seizures but produced binding alteration in the cerebellum and hippocampus with roughly 40% increase and 10% decrease, respectively. After convulsant BIC dose, which invariably led to generalized tonic-clonic seizures, binding increased 36% and 15% to cerebellar and striatal membranes respectively, but decreased 12% to hippocampal membranes. Kd value was accordingly modified: with the subconvulsant dose it decreased 27% in cerebellum whereas it increased 61% in hippocampus; with the convulsant dose, Kd value decreased 33% in cerebellum but increased 85% in hippocampus. No change in receptor number site was found, and Hill number was invariably close to unity. Conclusion Results indicate dissimilar central nervous system area susceptibility of muscarinic receptor to BIC. Ligand binding was modified not only by a convulsant BIC dose but also by a subconvulsant dose, indicating that changes are not attributable to the seizure process

  19. Infectious exposure in the first years of life and risk of central nervous system tumours in children: analysis of birth order, childcare attendance and seasonality of birth

    DEFF Research Database (Denmark)

    Schmidt, L S; Kamper-Jørgensen, M; Schmiegelow, K

    2010-01-01

    An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease....

  20. CNS manifestation in progressive facial hemiatrophy (Romberg's disease). MRI findings and review of the literature

    International Nuclear Information System (INIS)

    Terstegge, K.; Henkes, H.; Kern, A.

    1993-01-01

    In this article the authors describe the clinical and MR imaging findings of the CNS in three female patients with PFH and present a comprehensive review of the literature. One of three PFH patients had partial epilepsy. MRI showed ventricular enlargement, white matter lesions, flattening of the cortical surface and meningeal adhesions homolateral to the facial hemiatrophy. Two other patients had completely normal intracranial findings. These findings confirm that cerebral hemiatrophy can occur in a subgroup of PFH patients. The MRI pattern, however, does not seem to be consistent with a simple atrophic or malnutrition process. The authors consider chronic localized meningoencephalitis with vascular involvement as a possible underlying mechanism for the occasional CNS involvement in PFH. (orig./MG) [de

  1. Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood–brain barrier through paracellular transmigration and ERK activation

    Directory of Open Access Journals (Sweden)

    Sagar Divya

    2012-10-01

    Full Text Available Abstract Background Transmigration of circulating dendritic cells (DCs into the central nervous system (CNS across the blood–brain barrier (BBB has not thus far been investigated. An increase in immune cell infiltration across the BBB, uncontrolled activation and antigen presentation are influenced by chemokines. Chemokine ligand 2 (CCL2 is a potent chemoattractant known to be secreted by the BBB but has not been implicated in the recruitment of DCs specifically at the BBB. Methods Experimental autoimmune encephalomyelitis (EAE was induced in C57BL/6 mice by injection of MOG35–55 peptide and pertussis toxin intraperitoneally. Animals with increasing degree of EAE score were sacrificed and subjected to near-infrared and fluorescence imaging analysis to detect and localize the accumulation of CD11c+-labeled DCs with respect to CCL2 expression. To further characterize the direct effect of CCL2 in DC trafficking at the BBB, we utilized an in vitro BBB model consisting of human brain microvascular endothelial cells to compare migratory patterns of monocyte-derived dendritic cells, CD4+ and CD8+ T cells. Further, this model was used to image transmigration using fluorescence microcopy and to assess specific molecular signaling pathways involved in transmigration. Results Near-infrared imaging of DC transmigration correlated with the severity of inflammation during EAE. Ex vivo histology confirmed the presence of CCL2 in EAE lesions, with DCs emerging from perivascular spaces. DCs exhibited more efficient transmigration than T cells in BBB model studies. These observations correlated with transwell imaging, which indicated a paracellular versus transcellular pattern of migration by DCs and T cells. Moreover, at the molecular level, CCL2 seems to facilitate DC transmigration in an ERK1/2-dependent manner. Conclusion CNS recruitment of DCs correlates with disease severity in EAE via CCL2 chemotaxis and paracellular transmigration across the BBB

  2. Central nervous system frontiers for the use of erythropoietin

    DEFF Research Database (Denmark)

    Olsen, Niels Vidiendal

    2003-01-01

    Recombinant human erythropoietin (r-HuEPO; epoetin alfa) is well established as safe and effective for the treatment of anemia. In addition to the erythropoietic effects of endogenous erythropoietin (EPO), recent evidence suggests that it may elicit a neuroprotective effect in the central nervous...... system (CNS). Preclinical studies have demonstrated the presence of EPO receptors in the brain that are up-regulated under hypoxic or ischemic conditions. Intracerebral and systemic administration of epoetin alfa have been demonstrated to elicit marked neuroprotective effects in multiple preclinical...

  3. Neurotransmitter synthesis from CNS glutamine for central control of breathing

    International Nuclear Information System (INIS)

    Hoop, B.; Systrom, D.; Chiang, C.H.; Shih, V.E.; Kazemi, H.

    1986-01-01

    The maximum rate at which CNS glutamine (GLN) derived from glutamate (GLU) can be sequestered for synthesis of neurotransmitter GLU and/or γ-aminobutyric acid (GABA) has been determined in pentobarbital-anesthetized dogs. A total of 57 animals were studied under normal, hypoxic (Pa/sub O2/ greater than or equal to 20 mmHg), or hypercapnic (Pa/sub CO2/ less than or equal to 71 mm Hg) conditions. Thirteen of these were bilaterally vagotomized and carotid body denervated and studied only under normoxic or hypoxic conditions. In 5 animals cerebrospinal fluid GLN transfer rate constant k was measured using 13 N-ammonia tracer. Measured cerebral cortical (CC) and medullary (MED) GLN concentrations c are found to vary with GLU metabolic rate r according to c-C/sub m/r/(r+R), where r, the product of k and corresponding tissue GLU concentration, is assumed equal to the maximum GLN metabolic rate via pathways other than for neurotransmitter synthesis. The constants C/sub m/ and R are the predicted maximum GLN concentration and its maximum rate of sequestration for neurotransmitter synthesis, respectively. For both CNS tissue types in all animals, C/sub m/ = 20.9 +- 7.4 (SD) mmoles/kg wet wt(mM) and R = 6.2 +- 2.3 mM/min. These values are consistent with results obtained in anesthetized rats

  4. Human spinal locomotor control is based on flexibly organized burst generators

    OpenAIRE

    Danner, Simon M.; Hofstoetter, Ursula S.; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

    2015-01-01

    Understanding the organisation of human spinal locomotor circuitry after severe CNS damage is essential for improving neurorehabilitation strategies. Danner et al. present evidence of flexibly organised burst-generating elements within the functionally isolated human lumbosacral spinal cord that generate rhythmic patterns in response to constant, repetitive epidural stimulation.

  5. Fifth CNS international steam generator conference

    International Nuclear Information System (INIS)

    2006-01-01

    The Fifth CNS International Steam Generator Conference was held on November 26-29, 2006 in Toronto, Ontario, Canada. In contrast with other conferences which focus on specific aspects, this conference provided a wide ranging forum on nuclear steam generator technology from life-cycle management to inspection and maintenance, functional and structural performance characteristics to design architecture. The 5th conference has adopted the theme: 'Management of Real-Life Equipment Conditions and Solutions for the Future'. This theme is appropriate at a time of transition in the industry when plants are looking to optimize the performance of existing assets, prevent costly degradation and unavailability, while looking ahead for new steam generator investments in life-extension, replacements and new-build. More than 50 technical papers were presented in sessions that gave an insight to the scope: life management strategies; fouling, cleaning and chemistry; replacement strategies and new build design; materials degradation; condition assessment/fitness for service; inspection advancements and experience; and thermal hydraulic performance

  6. Human performance modeling for system of systems analytics.

    Energy Technology Data Exchange (ETDEWEB)

    Dixon, Kevin R.; Lawton, Craig R.; Basilico, Justin Derrick; Longsine, Dennis E. (INTERA, Inc., Austin, TX); Forsythe, James Chris; Gauthier, John Henry; Le, Hai D.

    2008-10-01

    A Laboratory-Directed Research and Development project was initiated in 2005 to investigate Human Performance Modeling in a System of Systems analytic environment. SAND2006-6569 and SAND2006-7911 document interim results from this effort; this report documents the final results. The problem is difficult because of the number of humans involved in a System of Systems environment and the generally poorly defined nature of the tasks that each human must perform. A two-pronged strategy was followed: one prong was to develop human models using a probability-based method similar to that first developed for relatively well-understood probability based performance modeling; another prong was to investigate more state-of-art human cognition models. The probability-based modeling resulted in a comprehensive addition of human-modeling capability to the existing SoSAT computer program. The cognitive modeling resulted in an increased understanding of what is necessary to incorporate cognition-based models to a System of Systems analytic environment.

  7. A Comparison of the Anorexic Effects of Chicken, Porcine, Human and Bovine Insulin on the Central Nervous System of Chicks

    Science.gov (United States)

    The aim of the present study was to determine if some naturally-occurring substitutions of amino acid residues of insulin could act differentially within the central nervous system (CNS) of neonatal chicks to control ingestive behavior. Intracerebroventricular (ICV) administration of chicken insuli...

  8. Toxicity, biodistribution and radioprotective capacity of l-homocysteine thiolactone in CNS tissues and tumors in rodents: comparison with prior results with phosphorothioates

    International Nuclear Information System (INIS)

    Spence, Alexander M.; Rasey, Janet S.; Dwyer-Hansen, Lori; Grunbaum, Zdenka; Livesey, John; Chin, Lay; Nelson, Norma; Stein, Donna; Krohn, Kenneth A.; Ali-Osman, Francis

    1995-01-01

    l-Homocysteine thiolactone (L-HCTL) was evaluated for its potential as an intravenously-administered central nervous system (CNS) radioprotector in C3H mice and F344 rats. Toxicity assessments in the mouse yielded a LD 50 of 297 mg/kg and in the rat 389 mg/kg. Biodistribution studies in tumor-bearing mice showed that brain specimens contained more label at 10 min than the tumors but less at 30 or 60 min. Brain uptake relative to the tumors, the brain/tumor ratio, ranged between 0.5 and 3.3. The cervical spinal cord of non-tumor-bearing rats was irradiated with 32 Gy 137 Cs with or without prior treatment with l-HCTL following which the time to forelimb or hindlimb paralysis was measured to determine the relative protective factors (RPFs) for this radiation dose. For forelimb paralysis the RPF was 1.9 (± 1.0, SD) and for hindlimb it was 2.0 (± 1.1, SD). 36B-10 glioma cells irradiated in vitro with or without l-HCTL and assayed for colony forming capacity demonstrated a dose modifying factor (DMF) of only 1.15 (± 0.16, SE). Rats bearing intracerebral 36B-10 glioma received 137 Cs irradiation with or without l-HCTL after which the tumors were similarly assayed in vitro. From this the glioma DMF was 1.2 (± 0.30, SE). Compared to prior results with phosphorothioates our data show that the toxicity of l-HCTL is roughly the same as WR2721, WR77913 and WR3689 and that it distributes at higher levels in the CNS after systemic administration. l-HCTL may well equal these phosphorothioates at protecting normal CNS tissue without requiring administration directly into the cerebrospinal fluid-containing spaces and it does not protect the 36B-10 glioma

  9. Dendrimer advances for the central nervous system delivery of therapeutics.

    Science.gov (United States)

    Xu, Leyuan; Zhang, Hao; Wu, Yue

    2014-01-15

    The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included.

  10. What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? A theoretical approach.

    Directory of Open Access Journals (Sweden)

    Taylor Chomiak

    2009-11-01

    Full Text Available The biological process underlying axonal myelination is complex and often prone to injury and disease. The ratio of the inner axonal diameter to the total outer diameter or g-ratio is widely utilized as a functional and structural index of optimal axonal myelination. Based on the speed of fiber conduction, Rushton was the first to derive a theoretical estimate of the optimal g-ratio of 0.6 [1]. This theoretical limit nicely explains the experimental data for myelinated axons obtained for some peripheral fibers but appears significantly lower than that found for CNS fibers. This is, however, hardly surprising given that in the CNS, axonal myelination must achieve multiple goals including reducing conduction delays, promoting conduction fidelity, lowering energy costs, and saving space.In this study we explore the notion that a balanced set-point can be achieved at a functional level as the micro-structure of individual axons becomes optimized, particularly for the central system where axons tend to be smaller and their myelin sheath thinner. We used an intuitive yet novel theoretical approach based on the fundamental biophysical properties describing axonal structure and function to show that an optimal g-ratio can be defined for the central nervous system (approximately 0.77. Furthermore, by reducing the influence of volume constraints on structural design by about 40%, this approach can also predict the g-ratio observed in some peripheral fibers (approximately 0.6.These results support the notion of optimization theory in nervous system design and construction and may also help explain why the central and peripheral systems have evolved different g-ratios as a result of volume constraints.

  11. What is the optimal value of the g-ratio for myelinated fibers in the rat CNS? A theoretical approach.

    Science.gov (United States)

    Chomiak, Taylor; Hu, Bin

    2009-11-13

    The biological process underlying axonal myelination is complex and often prone to injury and disease. The ratio of the inner axonal diameter to the total outer diameter or g-ratio is widely utilized as a functional and structural index of optimal axonal myelination. Based on the speed of fiber conduction, Rushton was the first to derive a theoretical estimate of the optimal g-ratio of 0.6 [1]. This theoretical limit nicely explains the experimental data for myelinated axons obtained for some peripheral fibers but appears significantly lower than that found for CNS fibers. This is, however, hardly surprising given that in the CNS, axonal myelination must achieve multiple goals including reducing conduction delays, promoting conduction fidelity, lowering energy costs, and saving space. In this study we explore the notion that a balanced set-point can be achieved at a functional level as the micro-structure of individual axons becomes optimized, particularly for the central system where axons tend to be smaller and their myelin sheath thinner. We used an intuitive yet novel theoretical approach based on the fundamental biophysical properties describing axonal structure and function to show that an optimal g-ratio can be defined for the central nervous system (approximately 0.77). Furthermore, by reducing the influence of volume constraints on structural design by about 40%, this approach can also predict the g-ratio observed in some peripheral fibers (approximately 0.6). These results support the notion of optimization theory in nervous system design and construction and may also help explain why the central and peripheral systems have evolved different g-ratios as a result of volume constraints.

  12. CCL2 binding is CCR2 independent in primary adult human astrocytes.

    Science.gov (United States)

    Fouillet, A; Mawson, J; Suliman, O; Sharrack, B; Romero, I A; Woodroofe, M N

    2012-02-09

    Chemokines are low relative molecular mass proteins, which have chemoattractant actions on many cell types. The chemokine, CCL2, has been shown to play a major role in the recruitment of monocytes in central nervous system (CNS) lesions in multiple sclerosis (MS). Since resident astrocytes constitute a major source of chemokine synthesis including CCL2, we were interested to assess the regulation of CCL2 by astrocytes. We showed that CCL2 bound to the cell surface of astrocytes and binding was not modulated by inflammatory conditions. However, CCR2 protein was not detected nor was activation of the classical CCR2 downstream signaling pathways. Recent studies have shown that non-signaling decoy chemokine receptors bind and modulate the expression of chemokines at site of inflammation. Here, we show that the D6 chemokine decoy receptor is constitutively expressed by primary human adult astrocytes at both mRNA and protein level. In addition, CCL3, which binds to D6, but not CCL19, which does not bind to D6, displaced CCL2 binding to astrocytes; indicating that CCL2 may bind to this cell type via the D6 receptor. Our results suggest that CCL2 binding to primary adult human astrocytes is CCR2-independent and is likely to be mediated via the D6 decoy chemokine receptor. Therefore we propose that astrocytes are implicated in both the establishment of chemokine gradients for the migration of leukocytes into and within the CNS and in the regulation of CCL2 levels at inflammatory sites in the CNS. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. Resveratrol Neuroprotection in Stroke and Traumatic CNS injury

    Science.gov (United States)

    Lopez, Mary; Dempsey, Robert J; Vemuganti, Raghu

    2015-01-01

    Resveratrol, a stilbene formed in many plants in response to various stressors, elicits multiple beneficial effects in vertebrates. Particularly, resveratrol was shown to have therapeutic properties in cancer, atherosclerosis and neurodegeneration. Resveratrol-induced benefits are modulated by multiple synergistic pathways that control oxidative stress, inflammation and cell death. Despite the lack of a definitive mechanism, both in vivo and in vitro studies suggest that resveratrol can induce a neuroprotective state when administered acutely or prior to experimental injury to the CNS. In this review, we discuss the neuroprotective potential of resveratrol in stroke, traumatic brain injury and spinal cord injury, with a focus on the molecular pathways responsible for this protection. PMID:26277384

  14. Possible role of glial cells in the relationship between thyroid dysfunction and mental disorders

    OpenAIRE

    Noda, Mami

    2015-01-01

    It is widely accepted that there is a close relationship between the endocrine system and the central nervous system (CNS). Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the development and function of the CNS; not only for neuronal cells but also for glial development and differentiation. Any impairment of TH supply to the developing CNS causes severe and irreversible changes in the overall architecture and function of the human brain, leading ...

  15. Radiotherapy of the central nervous system in acute leukemia

    International Nuclear Information System (INIS)

    Novak, L.J.

    1989-01-01

    The central nervous system (CNS) is a site of occult and overt involvement with acute lymphoblastic leukemia (ALL) in children. Prophylactic treatment of the cranial and spinal meninges can significantly reduce the incidence of CNS relapse. This review addresses the issues associated with the role of radiation therapy in the treatment of the CNS in ALL.20 references

  16. Combined small-molecule inhibition accelerates the derivation of functional, early-born, cortical neurons from human pluripotent stem cells

    Science.gov (United States)

    Qi, Yuchen; Zhang, Xin-Jun; Renier, Nicolas; Wu, Zhuhao; Atkin, Talia; Sun, Ziyi; Ozair, M. Zeeshan; Tchieu, Jason; Zimmer, Bastian; Fattahi, Faranak; Ganat, Yosif; Azevedo, Ricardo; Zeltner, Nadja; Brivanlou, Ali H.; Karayiorgou, Maria; Gogos, Joseph; Tomishima, Mark; Tessier-Lavigne, Marc; Shi, Song-Hai; Studer, Lorenz

    2017-01-01

    Considerable progress has been made in converting human pluripotent stem cells (hPSCs) into functional neurons. However, the protracted timing of human neuron specification and functional maturation remains a key challenge that hampers the routine application of hPSC-derived lineages in disease modeling and regenerative medicine. Using a combinatorial small-molecule screen, we previously identified conditions for the rapid differentiation of hPSCs into peripheral sensory neurons. Here we generalize the approach to central nervous system (CNS) fates by developing a small-molecule approach for accelerated induction of early-born cortical neurons. Combinatorial application of 6 pathway inhibitors induces post-mitotic cortical neurons with functional electrophysiological properties by day 16 of differentiation, in the absence of glial cell co-culture. The resulting neurons, transplanted at 8 days of differentiation into the postnatal mouse cortex, are functional and establish long-distance projections, as shown using iDISCO whole brain imaging. Accelerated differentiation into cortical neuron fates should facilitate hPSC-based strategies for disease modeling and cell therapy in CNS disorders. PMID:28112759

  17. The Role of Abcb5 Alleles in Susceptibility to Haloperidol-Induced Toxicity in Mice and Humans

    Science.gov (United States)

    Zheng, Ming; Zhang, Haili; Dill, David L.; Clark, J. David; Tu, Susan; Yablonovitch, Arielle L.; Tan, Meng How; Zhang, Rui; Rujescu, Dan; Wu, Manhong; Tessarollo, Lino; Vieira, Wilfred; Gottesman, Michael M.; Deng, Suhua; Eberlin, Livia S.; Zare, Richard N.; Billard, Jean-Martin; Gillet, Jean-Pierre; Li, Jin Billy; Peltz, Gary

    2015-01-01

    Background We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study. Methods and Findings A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered

  18. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

    KAUST Repository

    Zheng, Ming

    2015-02-03

    We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to

  19. Human factors information system

    International Nuclear Information System (INIS)

    Goodman, P.C.; DiPalo, C.A.

    1991-01-01

    Nuclear power plant safety is dependent upon human performance related to plant operations. To provide improvements in human performance, data collection and assessment play key roles. This paper reports on the Human factors Information System (HFIS) which is designed to meet the needs of the human factors specialists of the United States Nuclear Regulatory Commission. These specialists identify personnel errors and provide guidance designed to prevent such errors. HFIS is a simple and modular system designed for use on a personal computer. It is designed to contain four separate modules that provide information indicative of program or function effectiveness as well as safety-related human performance based on programmatic and performance data. These modules include the Human Factors Status module; the Regulatory Programs module; the Licensee Event Report module; and the Operator Requalification Performance module. Information form these modules can either be used separately or can be combined due to the integrated nature of the system. HFIS has the capability, therefore, to provide insights into those areas of human factors that can reduce the probability of events caused by personnel error at nuclear power plants and promote the health and safety of the public. This information system concept can be applied to other industries as well as the nuclear industry

  20. Methodological aspects in quantitative translational neuroimaging in central nervous system diseases with Positron Emission Tomography

    International Nuclear Information System (INIS)

    Müllauer, J.

    2013-01-01

    Patients suffering from central nervous system (CNS) diseases crucially depend on a sufficient supply with CNS active drugs that help them to control and endure their illness. As the site of action of CNS drugs is in the brain, these substances need to pass the blood-brain barrier (BBB), a physiological barrier seperating the blood circulation and the brain. However, CNS drug treatment is often accompanied by pharmacoresistance (drug resistance). Multidrug transporters, such as permeable glycoprotein (Pgp) are responsible for a gradient dependent transport of substances over the BBB. Drug resistance is hypothesised as a result of overactivity of multidrug transporters at the BBB, with the result of insufficient and poor CNS drug levels in the brain. In the case of epilepsy in up to 20 - 40% of patients drug resistance is observed. The influence of Ppg overexpression on drug resistance in epilepsy was studied using positron emission tomography (PET), a novel non-invasive nuclear imaging method, together with radioligands that interact with Pgp. Radiolabeled Pgp-substrates ((R)-[11C]verapamil), and inhibitors ([11C]elacridar and [11C]tariquidar) were developed and used to study the influence of Pgp and other transporters at the BBB in a translational research approach; in animal models of epilepsy and in humans. The aim in translational PET research is a direct comparision of gathered animal and human data. Consequently diverse methodological challenges arise, that need to be addressed and observed in order to enable a translation between species. To achieve full quantification of the function and density of drug transporters at the BBB in both, humans and rodents, kinetic modeling (compartmental modeling) was applied to the PET pharmacokinetic data. Estimated modeling parameters were in succession used to estimate biological and physiological processes of Pgp at the BBB. Subsequently, nonlinear mixed effects modeling was deployed to increase the mechanistic

  1. Strength analysis of CARR-CNS with crescent-shape moderator cell and helium sub-cooling jacket covering cell

    International Nuclear Information System (INIS)

    Yu Qingfeng; Feng Quanke; Kawai Takeshi; Shen Feng; Yuan Luzheng; Cheng Liang

    2005-01-01

    The new type of the moderator cell was developed for the cold neutron source (CNS) of the China Advanced Research Reactor (CARR) which is now being constructed at the China Institute of Atomic Energy in Beijing. A crescent-shape moderator cell covered by the helium sub-cooling jacket is adopted. The structure of the moderator cell is optimized by the stress FEM analysis. A crescent-shape would help to increase the volume of the moderator cell for fitting it to the four cold neutron guide tubes, even if liquid hydrogen, not liquid deuterium, was used as a cold moderator. The helium sub-cooling jacket covering the moderator cell removes the nuclear heating of the outer shell wall of the cell. It contributes to reduce the void fraction of liquid hydrogen in the outer shell of the moderator cell. Such a type of a moderator cell is suitable for the CNS with higher nuclear heating. The cold helium gas flows down first into the helium sub-cooling jacket and then flows up to the condenser. The theory of the self-regulation suitable to the thermo-siphon type of the CNS is also applicable and validated

  2. TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice

    DEFF Research Database (Denmark)

    Reinert, Line; Harder, Louis Andreas; Holm, Christian

    2012-01-01

    Herpes simplex viruses (HSVs) are highly prevalent neurotropic viruses. While they can replicate lytically in cells of the epithelial lineage, causing lesions on mucocutaneous surfaces, HSVs also establish latent infections in neurons, which act as reservoirs of virus for subsequent reactivation......, it is not known what cell type mediates the role of TLR3 in the immunological control of HSV, and it is not known whether TLR3 sensing occurs prior to or after CNS entry. Here, we show that in mice TLR3 provides early control of HSV-2 infection immediately after entry into the CNS by mediating type I IFN...... responses in astrocytes. Tlr3-/- mice were hypersusceptible to HSV-2 infection in the CNS after vaginal inoculation. HSV-2 exhibited broader neurotropism in Tlr3-/- mice than it did in WT mice, with astrocytes being most abundantly infected. Tlr3-/- mice did not exhibit a global defect in innate immune...

  3. Dendrimer Advances for the Central Nervous System Delivery of Therapeutics

    Science.gov (United States)

    2013-01-01

    The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included. PMID:24274162

  4. Metallothionein 1+2 protect the CNS during neuroglial degeneration induced by 6-aminonicotinamide

    DEFF Research Database (Denmark)

    Penkowa, Milena; Giralt, Mercedes; Camats, Jordi

    2002-01-01

    6-Aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes. Metallothionein 1+2 (MT-1+2) are neuroprotective factors in the central nervous system (CNS), and to determine the roles for MT after 6-AN, we have examined transgenic mice overexpressing MT-1...... (NITT), and the number of terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine triphosphate [dUTP]-digoxigenin nick end labeling-positive (TUNEL+), caspase-3+ apoptotic cells were significantly increased in the brainstem of normal mice after 6-AN. In the TgMTI* mice, the 6-AN-induced tissue...... damage was decreased in comparison to control mice, and they showed significantly reduced numbers of recruited macrophages and T lymphocytes, and a drastic reduction of oxidative stress and apoptotic cell death. In addition, the accompanying reactive astrogliosis was increased in the transgenic mice...

  5. Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis.

    Science.gov (United States)

    Jordan, Sabine D; Könner, A Christine; Brüning, Jens C

    2010-10-01

    The central nervous system (CNS) is capable of gathering information on the body's nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.

  6. The transition from day-to-night activity is a risk factor for the development of CNS oxygen toxicity in the diurnal fat sand rat (Psammomys obesus).

    Science.gov (United States)

    Eynan, Mirit; Biram, Adi; Mullokandov, Michael; Kronfeld-Schor, Noga; Paz-Cohen, Rotem; Menajem, Dvir; Arieli, Yehuda

    2017-01-01

    Performance and safety are impaired in employees engaged in shift work. Combat divers who use closed-circuit oxygen diving apparatus undergo part of their training during the night hours. The greatest risk involved in diving with such apparatus is the development of central nervous system oxygen toxicity (CNS-OT). We investigated whether the switch from day-to-night activity may be a risk factor for the development of CNS-OT using a diurnal animal model, the fat sand rat (Psammomys obesus). Animals were kept on a 12:12 light-dark schedule (6 a.m. to 6 p.m. at 500 lx). The study included two groups: (1) Control group: animals were kept awake and active during the day, between 09:00 and 15:00. (2) Experimental group: animals were kept awake and active during the night, between 21:00 and 03:00, when they were exposed to dim light in order to simulate the conditions prevalent during combat diver training. This continued for a period of 3 weeks, 5 days a week. On completion of this phase, 6-sulphatoxymelatonin (6-SMT) levels in urine were determined over a period of 24 h. Animals were then exposed to hyperbaric oxygen (HBO). To investigate the effect of acute melatonin administration, melatonin (50 mg/kg) or its vehicle was administered to the animals in both groups 20 min prior to HBO exposure. After the exposure, the activity of superoxide dismutase, catalase and glutathione peroxidase was measured, as were the levels of neuronal nitric oxide synthase (nNOS) and overall nitrotyrosylation in the cortex and hippocampus. Latency to CNS-OT was significantly reduced after the transition from day-to-night activity. This was associated with alterations in the level of melatonin metabolites secreted in the urine. Acute melatonin administration had no effect on latency to CNS-OT in either of the groups. Nevertheless, the activity of superoxide dismutase and catalase, as well as nitrotyrosine and nNOS levels, were altered in the hippocampus following melatonin

  7. The role of the immune system in central nervous system plasticity after acute injury.

    Science.gov (United States)

    Peruzzotti-Jametti, Luca; Donegá, Matteo; Giusto, Elena; Mallucci, Giulia; Marchetti, Bianca; Pluchino, Stefano

    2014-12-26

    Acute brain injuries cause rapid cell death that activates bidirectional crosstalk between the injured brain and the immune system. In the acute phase, the damaged CNS activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, thus bringing the inflammatory reaction to a close. In the chronic phase, a sustained immune activation has been described in many CNS disorders, and the degree of this prolonged response has variable effects on spontaneous brain regenerative processes. The challenge for treating acute CNS damage is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury. Herein we have reviewed the available information regarding the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that are associated with intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Genetic prion disease: no role for the immune system in disease pathogenesis?

    Science.gov (United States)

    Friedman-Levi, Yael; Binyamin, Orli; Frid, Kati; Ovadia, Haim; Gabizon, Ruth

    2014-08-01

    Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Identification of single nucleotide polymorphisms of the PI3K-AKT-mTOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

    Science.gov (United States)

    Le Rhun, Emilie; Bertrand, Nicolas; Dumont, Aurélie; Tresch, Emmanuelle; Le Deley, Marie-Cécile; Mailliez, Audrey; Preusser, Matthias; Weller, Michael; Revillion, Françoise; Bonneterre, Jacques

    2017-12-01

    The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients. The GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B-cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

    DEFF Research Database (Denmark)

    El-Galaly, Tarec Christoffer; Cheah, Chan Y; Hutchings, Martin

    2016-01-01

    progression-free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL...

  11. Human Factors Interface with Systems Engineering for NASA Human Spaceflights

    Science.gov (United States)

    Wong, Douglas T.

    2009-01-01

    This paper summarizes the past and present successes of the Habitability and Human Factors Branch (HHFB) at NASA Johnson Space Center s Space Life Sciences Directorate (SLSD) in including the Human-As-A-System (HAAS) model in many NASA programs and what steps to be taken to integrate the Human-Centered Design Philosophy (HCDP) into NASA s Systems Engineering (SE) process. The HAAS model stresses systems are ultimately designed for the humans; the humans should therefore be considered as a system within the systems. Therefore, the model places strong emphasis on human factors engineering. Since 1987, the HHFB has been engaging with many major NASA programs with much success. The HHFB helped create the NASA Standard 3000 (a human factors engineering practice guide) and the Human Systems Integration Requirements document. These efforts resulted in the HAAS model being included in many NASA programs. As an example, the HAAS model has been successfully introduced into the programmatic and systems engineering structures of the International Space Station Program (ISSP). Success in the ISSP caused other NASA programs to recognize the importance of the HAAS concept. Also due to this success, the HHFB helped update NASA s Systems Engineering Handbook in December 2007 to include HAAS as a recommended practice. Nonetheless, the HAAS model has yet to become an integral part of the NASA SE process. Besides continuing in integrating HAAS into current and future NASA programs, the HHFB will investigate incorporating the Human-Centered Design Philosophy (HCDP) into the NASA SE Handbook. The HCDP goes further than the HAAS model by emphasizing a holistic and iterative human-centered systems design concept.

  12. Gene expression in the muscle and central nervous system following intramuscular inoculation of encapsidated or naked poliovirus replicons

    International Nuclear Information System (INIS)

    Jackson, Cheryl A.; Messinger, Jeff; Palmer, Matthew T.; Peduzzi, Jean D.; Morrow, Casey D.

    2003-01-01

    The spread of intramuscularly inoculated poliovirus to the central nervous system (CNS) has been documented in humans, monkeys, and mice transgenic for the human poliovirus receptor. Poliovirus spread is thought to be due to infection of the peripheral nerve and retrograde transport of poliovirus through the axon to the neuron cell body, where final virus uncoating occurs and translation/replication ensues. In previous studies, we have shown that polio-based vectors (replicons) can be used for gene delivery to motor neurons of the CNS. Using a replicon that encodes green fluorescent protein (GFP), we found that following intrathecal inoculation, GFP expression was confined to motorneurons of the spinal cord. To further characterize the gene expression of poliovirus in the periphery and CNS, we have intramuscularly inoculated transgenic mice with poliovirus replicons encoding GFP. Expression of GFP was demonstrated in the muscle, sciatic nerve, dorsal root ganglion, and the ventral horn motorneurons following intramuscular inoculation. There was no evidence of paralysis or behavioral abnormalities in the mice following intramuscular inoculation of the replicon encoding GFP. Injection of replicon RNA alone (naked RNA) into the muscle of transgenic mice or rats, which do not express the poliovirus receptor, also resulted in expression of GFP in the muscle, sciatic nerve, dorsal root ganglion, and ventral horn motorneurons, indicating that transport of the replicon RNA from the periphery to CNS had occurred. GFP expression was found in the muscles and sciatic nerve as early as 6 h after injection of replicons or replicon RNA, even after sciatic nerve section. Analysis at longer times postinjection revealed GFP expression similar to 6 h levels in the cut sciatic nerves and robust expression in the nerves of uncut animals. The infection and expression of GFP in the CNS following intramuscular inoculation of encapsidated replicons encoding GFP occurred in juvenile or

  13. Fluids and barriers of the CNS: a historical viewpoint

    Directory of Open Access Journals (Sweden)

    Liddelow Shane A

    2011-01-01

    Full Text Available Abstract Tracing the exact origins of modern science can be a difficult but rewarding pursuit. It is possible for the astute reader to follow the background of any subject through the many important surviving texts from the classical and ancient world. While empirical investigations have been described by many since the time of Aristotle and scientific methods have been employed since the Middle Ages, the beginnings of modern science are generally accepted to have originated during the 'scientific revolution' of the 16th and 17th centuries in Europe. The scientific method is so fundamental to modern science that some philosophers consider earlier investigations as 'pre-science'. Notwithstanding this, the insight that can be gained from the study of the beginnings of a subject can prove important in the understanding of work more recently completed. As this journal undergoes an expansion in focus and nomenclature from cerebrospinal fluid (CSF into all barriers of the central nervous system (CNS, this review traces the history of both the blood-CSF and blood-brain barriers from as early as it was possible to find references, to the time when modern concepts were established at the beginning of the 20th century.

  14. CNS fungal meningitis to the "Top of the basilar"

    Institute of Scientific and Technical Information of China (English)

    Logan CS; Kirschner RC; Simonds GR

    2013-01-01

    Central nervous system(CNS) infections are a rare complication of epidural steroid injections and without strong clinical suspicion, fungal organisms may be overlooked among the long differential of causes of meningitis.Rare sequela of fungal meningitis is the development of stroke.To our knowledge, we present the first case of post epidural steroid injection(ESI) fungal meningitis leading toa basilar artery stroke, otherwise known as“top of the basilar” syndrome.We present a49-year-old female with a history ofESIs who presented to the emergency department with headache, neck stiffness, and abdominal pain.She was discharged after her labs and symptoms were deemed inconsistent with meningitis.She was eventually admitted and twelve days after her originalED visit, she was diagnosed with meningitis and started on anti-fungal treatment.She was discharged88 days later but was readmitted due to left sided weakness and mental status changes.She quickly lost motor and bulbar functions.AnMRA showed diminished distal flow through the basilar artery, suggesting near complete occlusion.Although appropriate long term anti-fungal treatment was started, the patient still succumbed to a rare vascular event.Physicians who are treating patients forESI meningitis should be aware of the potential for vasculitic and encephalitic complications.

  15. 6. CNS international conference on CANDU maintenance. Proceedings

    International Nuclear Information System (INIS)

    2003-01-01

    The 6th CNS International Conference on CANDU Maintenance took place in Toronto, Ontario on November 16-18, 2003. The theme for the conference was 'Maintenance for Life'. About 270 delegates attended the conference held by the Canadian Nuclear Society. The conference consisted of four parallel sessions, a pattern that continued throughout the conference. Papers were grouped under the following headings: Fuel Channels and End Fittings - Assessments; Fuel Channels and End Fittings - Inspections; Fuel Channels and End Fittings - Maintenance; Fuel Channels and End Fittings - Universal Delivery Machine; Water Upgrading; Performance and Plant Life Improvement; Steam Generator Life Management; Steam Generator Modifications; Steam Generators - Inspections; Steam Generators - Assessments; Maintenance Programs; Feeder Inspections; Feeder Assessment and Mitigation; Valve Maintenance; Instrumentation and Control; Inspection Technology; and Fuel Handling

  16. Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils.

    Science.gov (United States)

    Ayers, Jacob I; Brooks, Mieu M; Rutherford, Nicola J; Howard, Jasie K; Sorrentino, Zachary A; Riffe, Cara J; Giasson, Benoit I

    2017-01-15

    Misfolded α-synuclein (αS) is hypothesized to spread throughout the central nervous system (CNS) by neuronal connectivity leading to widespread pathology. Increasing evidence indicates that it also has the potential to invade the CNS via peripheral nerves in a prion-like manner. On the basis of the effectiveness following peripheral routes of prion administration, we extend our previous studies of CNS neuroinvasion in M83 αS transgenic mice following hind limb muscle (intramuscular [i.m.]) injection of αS fibrils by comparing various peripheral sites of inoculations with different αS protein preparations. Following intravenous injection in the tail veins of homozygous M83 transgenic (M83 +/+ ) mice, robust αS pathology was observed in the CNS without the development of motor impairments within the time frame examined. Intraperitoneal (i.p.) injections of αS fibrils in hemizygous M83 transgenic (M83 +/- ) mice resulted in CNS αS pathology associated with paralysis. Interestingly, injection with soluble, nonaggregated αS resulted in paralysis and pathology in only a subset of mice, whereas soluble Δ71-82 αS, human βS, and keyhole limpet hemocyanin (KLH) control proteins induced no symptoms or pathology. Intraperitoneal injection of αS fibrils also induced CNS αS pathology in another αS transgenic mouse line (M20), albeit less robustly in these mice. In comparison, i.m. injection of αS fibrils was more efficient in inducing CNS αS pathology in M83 mice than i.p. or tail vein injections. Furthermore, i.m. injection of soluble, nonaggregated αS in M83 +/- mice also induced paralysis and CNS αS pathology, although less efficiently. These results further demonstrate the prion-like characteristics of αS and reveal its efficiency to invade the CNS via multiple routes of peripheral administration. The misfolding and accumulation of α-synuclein (αS) inclusions are found in a number of neurodegenerative disorders and is a hallmark feature of Parkinson

  17. Electrical Stimulation Elicit Neural Stem Cells Activation:New Perspectives in CNS Repair

    Directory of Open Access Journals (Sweden)

    Ratrel eHuang

    2015-10-01

    Full Text Available Researchers are enthusiastically concerned about neural stem cell (NSC therapy in a wide array of diseases, including stroke, neurodegenerative disease, spinal cord injury (SCI and depression. Although enormous evidences have demonstrated that neurobehavioral improvement may benefit from NSC-supporting regeneration in animal models, approaches to endogenous and transplanted NSCs are blocked by hurdles of migration, proliferation, maturation and integration of NSCs. Electrical stimulation (ES may be a selective nondrug approach for mobilizing NSCs in the central nervous system (CNS. This technique is suitable for clinic application, because it is well established and its potential complications are manageable. Here, we provide a comprehensive review of the emerging positive role of different electrical cues in regulating NSC biology in vitro and in vivo, as well as biomaterial-based and chemical stimulation of NSCs. In the future, ES combined with stem cell therapy or other cues probably becomes an approach for promoting brain repair.

  18. Human Performance Evaluation System

    International Nuclear Information System (INIS)

    Hardwick, R.J. Jr.

    1985-01-01

    Operating nuclear power plants requires high standards of performance, extensive training and responsive management. Despite our best efforts inappropriate human actions do occur, but they can be managed. An extensive review of License Event Reports (LERs) was conducted which indicated continual inadequacy in human performance and in evaluation of root causes. Of some 31,000 LERs, about 5,000 or 16% were directly attributable to inappropriate actions. A recent analysis of 87 Significant Event Reports (issued by INPO in 1983) identified inappropriate actions as being the most frequent root cause (44% of the total). A more recent analysis of SERs issued in 1983 and 1984 indicate that 52% of the root causes were attributed to human performance. The Human Performance Evaluation System (HPES) is a comprehensive, coordinated utility/industry system for evaluating and reporting human performance situtations. HPES is a result of the realization that current reporting system provide limited treatment of human performance and rarely provide adequate information about root causes of inappropriate actions by individuals. The HPES was implemented to identify and eliminate root causes of inappropriate actions

  19. Evidence for differential changes of junctional complex proteins in murine neurocysticercosis dependent upon CNS vasculature.

    Science.gov (United States)

    Alvarez, Jorge I; Teale, Judy M

    2007-09-12

    The delicate balance required to maintain homeostasis of the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Upon injury, the BBB is disrupted compromising the CNS. BBB disruption has been represented as a uniform event. However, our group has shown in a murine model of neurocysticercosis (NCC) that BBB disruption varies depending upon the anatomical site/vascular bed analyzed. In this study further understanding of the mechanisms of BBB disruption was explored in blood vessels located in leptomeninges (pial vessels) and brain parenchyma (parenchymal vessels) by examining the expression of junctional complex proteins in murine brain infected with Mesocestoides corti. Both pial and parenchymal vessels from mock infected animals showed significant colocalization of junctional proteins and displayed an organized architecture. Upon infection, the patterned organization was disrupted and in some cases, particular tight junction and adherens junction proteins were undetectable or appeared to be undergoing proteolysis. The extent a